Oxazole derivatives, their production and use

ABSTRACT

A novel compound of the formula:                    
     wherein R 1  is a halogen atom, an optionally substituted heterocyclic, hydroxy, thiol or amino group; A is an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally esterified or amidated carboxy group; B is an optionally substituted aromatic group; Y is a divalent aliphatic hydrocarbon group, or a salt thereof, which have an excellent insulin secertion-promoting and blood sugar-depressing effect, and useful in agents for diabetes.

This application is a 371 of PCT/JP97/01146 filed Apr. 2, 1997.

TECHNICAL FIELD

The present invention relates to novel oxazole derivatives which areuseful for prophylaxis and therapy of diabetes.

BACKGROUND ART

As agents for diabetes, heretofore, various biguanide compounds andsulfonylurea compounds have been used. However, biguanide compounds arenot used at present, because these compounds induce undesirable sideeffects, such as lactic acidosis. Though having an excellent bloodsugar-depressing effect, sulfonylurea compounds require care in usesince they often induce grave hypoglycemia. Oxazole derivatives having ablood sugar-depressing effect and a sugar tolerance-improving effect aredescribed in, for example, EP-92239, JP59-190979 and EP-382199.

The object of the present invention is to provide novel compounds whichhave an insulin secretion-promoting effect and a blood sugar-depressingeffect, which are useful in agents for diabetes and which have lowtoxicity.

DISCLOSURE OF INVENTION

The novel oxazole derivatives represented by the following formula (I)have been found to possess an excellent blood sugar-depressing effectand insulin secretion-promoting effect. On the basis of this finding, wehave completed the present invention.

Specifically, the present invention provides a compound of the followinggeneral formula (I):

wherein R¹ represents a halogen atom, or an optionally substitutedheterocyclic group, an optionally substituted hydroxy group, anoptionally substituted thiol group or an optionally substituted aminogroup; A represents an optionally substituted acyl group, an optionallysubstituted heterocyclic group, an optionally substituted hydroxy group,or an optionally esterified or amidated carboxy group; B represents anoptionally substituted aromatic group; Y represents a divalent aliphatichydrocarbon group, or a salt thereof, and a pharmaceutical compositioncomprising the compound (I) or a pharmaceutically acceptable salt as anactive ingredient.

In the formula (I), the heterocyclic group of the optionally substitutedheterocyclic group represented by R¹ or A may be a 5- or 6-membered ringhaving 1 to 4 atoms selected from N, O and S as the ring-constitutingatoms other than carbon atom(s), or a condensed ring thereof. Thecondensed ring includes, for example, condensed rings comprising the 5-or 6-membered ring as condensed with any of a 6-membered ring having 1or 2 nitrogen(s), a benzene ring or a 5-membered ring having one sulfur.

Typical examples of the heterocyclic group include aromatic heterocyclicgroups such as pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrimidinyl (e.g. 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl),pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g.2-pyrazinyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl), imidazolyl (e.g.1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g.1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl,thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g.2-oxazolyl, 4-oxazolyl, 5-oxazolyl), 1,2,4-oxadiazolyl (e.g.1,2,4-oxadiazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl), 1,2,3-triazolyl (e.g. 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl),benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl), indolyl(e.g. indol-1-yl, indol-3-yl), 1H-indazolyl (e.g. 1H-indazol-1-yl),1H-pyrrolo[2,3-b]pyrazinyl (e.g. 1H-pyrrolo[2,3-b]pyrazin-1-yl),1H-pyrrolo[2,3-b]pyridyl (e.g. 1H-pyrrolo[2,3-b]pyridin-1-yl),1H-imidazo[4,5-b]pyridyl (e.g. 1H-imidazo[4,5-b]pyridin-1-yl),1H-imidazo[4,5-c]pyridyl (e.g. 1H-imidazo[4,5-c]pyridin-1-yl) and1H-imidazo[4,5-b]pyrazinyl (e.g. 1H-imidazo[4,5-b]pyrazin-1-yl), andnon-aromatic heterocyclic groups such as pyrrolidinyl (e.g.1-pyrrolidinyl), piperidinyl (e.g. piperidino), morpholinyl (e.g.morpholino), piperazinyl (e.g. 1-piperazinyl), hexamethyleneiminyl (e.g.hexamethyleneimin-1-yl), oxazolidinyl (e.g. oxazolidin-3-yl),thiazolidinyl (e.g. thiazolidin-3-yl, thiazolidin-2-yl), imidazolidinyl(e.g. imidazolidin-3-yl), imidazolinyl (e.g. imidazolin-1-yl,imidazolin-2-yl), oxazolinyl (e.g. oxazolin-2-yl), thiazolinyl (e.g.thiazolin-2-yl), and oxazinyl (e.g. oxazin-2-yl).

Preferred examples of the heterocyclic group are an azolyl group (e.g.pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl,oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl), an azolinyl group (e.g. imidazolinyl, oxazolinyl,thiazolinyl), an azolidinyl group (e.g. pyrrolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl).

The heterocyclic group represented by R¹ or A may have 1 to 3substituents at its substitutable positions. The substituents include,for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbongroup, an aryl group, an aromatic heterocyclic group, a non-aromaticheterocyclic group, a halogen atom, a nitro group, an optionallysubstituted amino group, an optionally substituted acyl group, anoptionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally esterified or amidated carboxy group and oxo group.

Examples of an azolidinyl group substituted by 1 or 2 oxo group(s) are2-oxoimidazolidinyl (e.g. 2-oxoimidazolidin-1-yl),2,4-dioxoimidazolidinyl (e.g. 2,4-dioxoimidazolidin-3-yl),2,4-dioxooxazolidinyl (e.g. 2,4-dioxooxazolidin-3-yl) or2,4-dioxothiazolidinyl (e.g. 2,4-dioxothiazolidin-3-yl).

The aliphatic hydrocarbon group may be a linear or branched aliphatichydrocarbon group having 1 to 15 carbon atoms such as, for example, analkyl group, an alkenyl group and an alkynyl group.

Preferred examples of the alkyl group are alkyl groups having 1 to 10carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,t-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl,octyl, nonyl and decyl.

Preferred examples of the alkenyl group are alkenyl groups having 2 to10 carbon atoms such as, for example, vinyl, allyl, isopropenyl,1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl and 5-hexenyl.

Preferred examples of the alkynyl group are alkynyl groups having 2 to10 carbon atoms such as, for example, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

The alicyclic hydrocarbon group may be a saturated or unsaturatedalicyclic hydrocarbon group having 3 to 12 carbon atoms such as, forexample, a cycloalkyl group, a cycloalkenyl group and a cycloalkadienylgroup.

Preferred examples of the cycloalkyl group are cycloalkyl groups having3 to 10 carbon atoms such as, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

Preferred examples of the cycloalkenyl group are cycloalkenyl groupshaving 3 to 10 carbon atoms such as, for example, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl.

Preferred examples of the cycloalkadienyl group are cycloalkadienylgroups having 4 to 10 carbon atoms such as, for example,2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and2,5-cyclohexadien-1-yl.

The aryl group stands for a mono-cyclic or condensed poly-cyclicaromatic hydrocarbon group, and preferred examples of them are arylgroups having 6 to 14 carbon atoms such as, for example, phenyl,naphthyl, anthryl, phenanthryl and acenaphthylenyl. More preferable arephenyl, 1-naphthyl and 2-naphthyl.

Preferred examples of the aromatic heterocyclic group include anaromatic mono-cyclic heterocyclic groups such as furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl, and an aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolidinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and1,2,4-triazolo[4,3-b]pyridazinyl.

Preferred examples of the non-aromatic heterocyclic group includeoxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, thioranyl,piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyland pyrrolidinyl.

Examples of the halogen atom include fluorine, chlorine, bromine andiodine. More preferably are fluorine and bromine.

The optionally substituted amino group may be an amino group (—NH₂)which may be mono- or di-substituted with, for example, an alkyl grouphaving 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbonatoms, a cycloalkyl group having 3 to 10 carbon atoms, an acyl grouphaving 1 to 10 carbon atoms (e.g. formyl, C₁₋₉ alkyl-carbonyl such asacetyl) or an aromatic group having 6 to 12 carbon atoms (e.g. C₆₋₁₂aryl such as phenyl). The substituted amino group includes, for example,methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino,diallylamino, cyclohexylamino, acetylamino, propionylamino,benzoylamino, phenylamino and N-methyl-N-phenylamino.

The acyl moiety of the optionally substituted acyl group may be an acylgroup having 1 to 13 carbon atoms, including, for example, a formylgroup, and a group to be formed by bonding between an alkyl group having1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, analkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3to 10 carbon atoms or an aromatic group from 6 to 12 carbon atoms and acarbonyl group (e.g., C₁₋₁₀ alkyl-carbonyl such as acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl; C₃₋₁₀ cycloalkyl-carbonyl such as cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl; C₂₋₁₀alkenyl-carbonyl such as crotonyl; C₃₋₁₀ cycloalkenyl-carbonyl such as2-cyclohexenecarbonyl; C₆₋₁₀ aryl-carbonyl such as benzoyl, nicotinoyl).The substituent of the substituted acyl group may include, for example,an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3carbon atoms, a halogen atom (e.g., chlorine, fluorine, bromine), anitro group, a hydroxy group and an amino group.

The substituted hydroxy group of the optionally substituted hydroxygroup includes, for example, an alkoxy group, an alkenyloxy group, anaralkyloxy group, an acyloxy group, an aryloxy group, analkylsulfonyloxy group and an arylsulfonyloxy group.

Preferred examples of the alkoxy group are alkoxy groups having 1 to 10carbon atoms such as, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy,neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxyand cyclohexyloxy.

Preferred examples of the alkenyloxy group are alkenyloxy groups having2 to 10 carbon atoms such as, for example, allyloxy, crotyloxy,2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and2-cyclohexenylmethoxy.

Preferred examples of the aralkyloxy group include aralkyloxy groupshaving 7 to 10 carbon atoms, for example, phenyl-C₁₋₄ alkyloxy group(e.g., benzyloxy, phenethyloxy).

Preferred examples of the acyloxy group include acyloxy groups having 2to 13 carbon atoms, more preferably alkanoyloxy groups having 2 to 4carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy).

Preferred examples of the aryloxy group are aryloxy groups having 6 to14 carbon atoms such as, for example, phenoxy and naphthyloxy. Thearyloxy group may have 1 or 2 substituents such as, for example, ahalogen atom (e.g., chlorine, fluorine, bromine), or an alkoxy grouphaving 1 to 4 carbon atoms. The substituted aryloxy group includes, forexample, 4-chlorophenoxy and 2-methoxyphenoxy.

Preferred examples of the alkylsulfonyloxy group are alkylsulfonyloxygroups having 1 to 10 carbon atoms such as, for example,methylsulfonyloxy and ethylsulfonyloxy.

Preferred examples of the arylsulfonyloxy are arylsulfonyloxy groupshaving 6 to 12 carbon atoms (which may be substituted by a C₁₋₆ alkyl)such as, for example, phenylsulfonyl, 4-methylsulfonyl.

The substituted thiol group (substituted mercapto group) of theoptionally substituted thiol group (optionally substituted mercaptogroup) includes, for example, an alkylthio group, an arylthio group, aheteroarylthio group, an aralkylthio group, a heteroarylalkylthio groupand an acylthio group.

Preferred examples of the alkylthio group are alkylthio groups having 1to 10 carbon atoms such as, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio,t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio,heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio.

Preferred examples of the arylthio group are arylthio groups having 6 to14 carbon atoms which may be substituted by a C₁₋₆ alkyl group such as,for example, phenylthio, 4-phenylthio and naphthylthio.

The heteroarylthio group includes, for example, thiol groups substitutedby any of the above-mentioned aromatic heterocyclic groups. Preferableexamples of them are 2-pyridylthio, 3-pyridylthio, 2-imidazolylthio and1,2,4-triazol-5-ylthio.

Preferred examples of the aralkylthio group are aralkylthio groupshaving 7 to 10 carbon atoms such as, for example, phenyl-C₁₋₄ alkylthiogroups (e.g., benzylthio, phenethylthio).

The heteroarylalkylthio group includes, for example, alkylthio groupssubstituted by any of the above-mentioned aromatic heterocyclic group.The alkylthio moiety of the heteroarylaklylthio group are the same asthe above-mentioned alkylthio group. Preferred examples of theheteroarylalkylthio group include pyridyl-C₁₋₄ alkylthio groups (e.g.,2-pyridylmethylthio, 3-pyridylmethylthio).

Preferred examples of the acylthio group are acylthio groups having 2 to13 carbon atoms, more preferably alkanoylthio groups having 2 to 4carbon atoms (e.g., acetylthio, propionylthio, butyrylthio,isobutytylthio).

The esterified carboxy group of the optionally esterified or amidatedcarboxy group includes, for example, an alkoxycarbonyl group, anaralkyloxycarbonyl group, an aryloxycarbonyl group and aheteroarylalkyloxycarbonyl.

Preferred examples of the alkoxycarbonyl group are alkoxycarbonyl groupshaving 2 to 5 carbon atoms such as, for example, C₁₋₄ alkoxy-carbonyl(e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andbutoxycarbonyl).

Preferred examples of the aralkyloxycarbonyl group arearalkyloxycarbonyl groups having 8 to 10 carbon atoms such as, forexample, C₇₋₉ aralkyloxy-carbonyl (e.g. benzyloxycarbonyl).

Preferred examples of the aryloxycarbonyl group are aryloxycarbonylgroups having 7 to 15 carbon atoms such as for example, C₆₋₁₄aryloxy-carbonyl (e.g. phenoxycarbonyl and p-tolyloxycarbonyl).

The heteroarylalkyloxycarbonyl group includes, for example,alkyloxycarbonyl groups substituted with any of the above-mentionedaromatic heterocyclic groups. The alkyloxycarbonyl moiety of theheteroarylalkyloxycarbonyl are the same as the above-mentionedalkoxycarbonyl. Preferred examples of the heteroarylalkyloxycarbonylgroup include pyridyl-C₁₋₄ alkoxy-carbonyl groups (e.g.,2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl).

The amidated carboxyl group of the optionally esterified or amidatedcarboxyl group includes, for example, a group of formula: —CON(R⁵) (R⁶),wherein R⁵ and R⁶ may be the same or different and each represents ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted hydroxy group or an optionally substitutedheterocyclic group. The hydrocarbon groups of the optionally substitutedhydrocarbon group represented by R⁵ or R⁶ includes, for example, analiphatic hydrocarbon group, an alicyclic hydrocarbon group and an arylgroup, which have been referred to hereinabove as the examples of thesubstituent for the heterocyclic group of R¹ or A. The substitutedhydroxy group of the optionally substituted hydroxy group represented byR⁵ or R⁶ may be the substituted hydroxy group of R¹ or A. Theheterocyclic group of the optionally substituted heterocyclic grouprepresented by R⁵ or R⁶ may be an aromatic heterocyclic group which isreferred to hereinabove as the examples of the substituent for theheterocyclic group of R¹ or A. Regarding the substituents of R⁵ or R⁶the group may be substituted by 1 to 3 substituents selected from ahalogen atom (e.g., chlorine, fluorine, bromine, iodine), an alkyl grouphaving 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbonatoms.

In the formula (I), an alicyclic hydrocarbon group, an aryl group, anaromatic heterocyclic group or a non-aromatic heterocyclic group for thesubstituent on the heterocyclic group may be substituted by one or more,preferably 1 to 3 suitable substituents. Such substituents include, forexample, an alkyl group having 1 to 6 carbon atoms, an alkenyl grouphaving 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms,a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to14 carbon atoms (e.g., phenyl, naphthyl), an aromatic heterocyclicgroup. (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl), anon-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino,piperidino, pyrrolidino, piperazino), an aralkyl group having 7 to 9carbon atoms (e.g. benzyl), an amino group, an N-mono(C₁₋₄)alkylaminogroup, an N,N-di(C₁₋₄)alkylamino group, an acylamino group having 2 to 8carbon atoms (e.g., C₁₋₇ alkyl-carbonylamino such as acetylamino,propionylamino; benzoylamino), an amidino group, an acyl group having 2to 8 carbon atoms (e.g., C₁₋₇ alkyl-carbonyl such as acetyl, benzoyl), acarbamoyl group, an N-mono(C₁₋₄)alkylcarbamoyl group, anN,N-di(C₁₋₄)alkylcarbamoyl group, a sulfamoyl group, anN-mono(C₁₋₄)alkylsulfamoyl group, an N,N-di(C₁₋₄)alkylsulfamoyl group, acarboxy group, an alkoxycarbonyl group having 2 to 8 carbon atoms, ahydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkenyloxygroup having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms (e.g.benzyloxy), an aryloxy group having 6 to 14 carbon atoms (e.g.,phenyloxy, naphthyloxy), a mercapto group, an alkylthio group having 1to 4 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms (e.g.benzylthio), an arylthio group having 6 to 14 carbon atoms (e.g.,phenylthio, naphthylthio), a sulfo group, a cyano group, an azido group,a nitro group, a nitroso group and a halogen atom (e.g., fluorine,chlorine, bromine, iodine).

In the formula (I), as the halogen atom, the optionally substitutedhydroxy group, the optionally substituted thiol group and the optionallysubstituted amino group represented by R¹, are those that are mentionedhereinabove as the examples of the substituents for the heterocyclicgroup represented by R¹ or A.

In the formula (I), R¹ is preferably an optionally substitutedheterocyclic group.

In the formula (I), as the optionally substituted acyl group, theoptionally substituted hydroxy group, and the optionally esterified oramidated carboxy group represented by A are those that are mentionedhereinabove as the examples of the substituents for the heterocyclicgroup represented by R¹ or A.

In the formula (I), A is preferably an optionally substitutedheterocyclic group or an optionally substituted hydroxy group.

In the formula (I), the aromatic group of the optionally substitutedaromatic group represented by B includes, for example, an aromatichydrocarbon group and an aromatic heterocyclic group.

Preferred examples of the aromatic hydrocarbon group are aromatichydrocarbon groups having 6 to 14 carbon atoms such as for example,C₆₋₁₄ aryl group such as phenyl and naphthyl.

Preferred examples of the aromatic heterocyclic group are those that arementioned hereinabove as the examples of the substituent for theheterocyclic group represented by R¹ or A. More preferable are furyl,thienyl, pyridyl and quinolyl.

Regarding the optionally substituted aromatic group represented by B, itmay be substituted by 1 to 3 substituents selected from, for example, ahalogen atom, a nitro group, a cyano group, an optionally substitutedalkoxy group, an optionally substituted alkyl group and an optionallysubstituted cycloalkyl group.

The halogen atom includes, for example, fluorine, chlorine, bromine andiodine.

Examples of the alkoxy group of the optionally substituted alkoxy groupare those that are mentioned hereinabove as the examples of thesubstituent for the heterocyclic group represented by R¹ or A. Morepreferable are linear or branched alkoxy groups having 1 to 6 carbonatoms.

Examples of the alkyl group of the optionally substituted alkyl groupare those that are mentioned hereinabove as the examples of thesubstituent for the heterocyclic group represented by R¹ or A. Morepreferable are linear or branched alkyl groups having 1 to 6 carbonatoms.

Examples of the cycloalkyl group of the optionally substitutedcycloalkyl group are those that are mentioned hereinabove as theexamples of the substituent for the heterocyclic group represented by R¹or A. More preferable are cycloalkyl groups having 3 to 7 carbon atoms.

Regarding the above-mentioned optionally substituted alkoxy, alkyl andcycloalkyl groups, each of these groups may be substituted by 1 to 3substituents selected from, for example, a halogen atom (e.g., fluorine,chlorine, bromine, iodine), a hydroxy group and an alkoxy group having 1to 6 carbon atoms.

The substituted alkoxy group includes, for example, trifluoromethoxy,difluoromethoxy, 2,2,2-trifluoroethoxy and 1,1-difluoroethoxy.

The substituted alkyl group includes, for example, trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 1-hydroxymethyl,methoxymethyl, ethoxymethyl, 2-methoxymethyl and 2,2-dimethoxyethyl.

In the formula (I), B is preferably an optionally substituted aromatichydrocarbon group, and more preferably an optionally substituted phenylgroup.

In the formula (I), the divalent aliphatic hydrocarbon group having 1 to7 carbon atoms represented by Y may be either linear or branched, andmay be either saturated or unsaturated. Typical examples of thealiphatic hydrocarbon group include saturated groups such as —CH₂—,—CH(CH₃)—, —(CH₂)₂—, —CH(C₂H₅)—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—and —(CH₂)₇—, and unsaturated groups such as —CH═CH—, —C(CH₃)═CH—,—CH═CH—CH₂—, —C(C₂H₅)═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—CH₂—,—CH═CH—CH═CH—CH₂— and —CH═CH—CH═CH— CH═CH—CH₂—. Y is preferably adivalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and ismore preferably the saturated one. Preferred examples of Y are —(CH₂)₃—and —(CH₂)₂—.

Preferred examples of the compound (I) of this invention are as follows.

(1) In the formula (I), R¹ is an optionally substituted heterocyclicgroup, and a preferred example of the heterocyclic group is a 5- or6-membered ring having 1 to 4 atoms selected from N, O and S as thering-constituting atoms other than carbon atom(s), or a condensed ringcomprising the 5- or 6-membered ring as condensed with any of a6-membered ring having 1 or 2 nitrogen, a benzene ring or a 5-memberedring having one sulfur, and a more preferred example of the heterocyclicgroup is an azolyl group.

(2) In the formula (I), A is an optionally substituted heterocyclicgroup, preferred example of the heterocyclic group is a 5- or 6-memberedring having 1 to 4 atoms selected from N, O and S as thering-constituting atoms other than carbon atom(s), or a condensed ringcomprising the 5- or 6-membered ring as condensed with a 6-membered ringhaving 1 or 2 nitrogen, a benzene ring or a 5-membered ring having onesulfur, and more preferred example of the heterocyclic group is anazolyl, azolinyl or azolidinyl group.

(3) In the formula (I), the optionally substituted heterocyclic grouprepresented by R¹ and A is a 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, benzimidazol-1-yl,benzimidazol-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-1-yl,1H-pyrrolo[2,3-b]pyrazin-1-yl, 1H-pyrrolo[2,3-b]pyridin-1-yl,1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,1H-imidazo[4,5-b]pyrazin-1-yl, 1-pyrrolidinyl, piperidino, morpholino,1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl,thiazolidin-3-yl, imidazolidin-3-yl, imidazolin-1-yl, imidazolin-2-yl,oxazolin-2-yl, thiazolin-2-yl, oxazin-2-yl, 2-oxoimidazolidin-1-yl,2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl or2,4-dioxothiazolidin-3-yl group which may be substituted by 1 to 3substituents selected from the group consisting of an aliphatichydrocarbon group, an alicyclic hydrocarbon group, an aryl group, anaromatic heterocyclic group, a non-aromatic heterocyclic group, ahalogen atom, a nitro group, an optionally substituted amino group, anoptionally substituted acyl group, an optionally substituted hydroxygroup, an optionally substituted thiol group and an optionallyesterified or amidated carboxy group.

(4) In the formula (I), A is an optionally substituted hydroxy group.

(5) In the formula (I), Y is a divalent aliphatic hydrocarbon grouphaving 1 to 7 carbon atoms, and more preferable a divalent aliphatichydrocarbon group having 2 to 4 carbon atoms.

(6) In the formula (I), R¹ is (i) halogen, (ii) a imidazolyl, pyrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, benzimidazolyl, pyrrolidinyl,piperidinyl, morphorinyl or hexamethyleneiminyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₁₀ alkyl, C₆₋₁₄ aryl and C₁₋₁₀ alkylthio, (iii) a C₁₋₁₀ alkoxy group,(iv) a C₆₋₁₄ aryloxy group, (v) a C₁₋₁₀ alkylthio group, (vi) a C₆₋₁₄arylthio which may be substituted by a C₁₋₆ alkyl, (vii) a thiol groupsubstituted by an imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl orpyridyl group which may be substituted by a C₁₋₆ alkyl or C₆₋₁₄ aryl,(viii) a pyridyl-C₁₋₄ alkylthio group, or (ix) an amino group which maybe substituted by 1 or 2 C₁₋₁₀ alkyl or C₃₋₁₀ cycloalkyl;

A is (i) formyl group, (ii) an imidazolyl, pyrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl,2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinylgroup which may be substituted by a C₁₋₁₀ alkyl group, (iii) hydroxygroup, (iv) a C₆₋₁₄ aryloxy group which may be substituted by a C₁₋₄alkoxy group, (v) a C₁₋₁₀ alkylsulfonyloxy group, (vi) a C₁₋₄alkoxy-carbonyl group, (vii) a C₇₋₉ aralkyloxy-carbonyl group, or (viii)a group of the formula: —CON(R⁵)(R⁶), wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₁₀ alkyl which may be substituted by ahalogen atom or a C₁₋₁₀ alkoxy group;

B is a phenyl group which may be substituted by a halogen; Y is—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— or —(CH₂)₆—.

(7) In the formula (I), R¹ is an optionally substituted heterocyclicgroup; A is an optionally substituted heterocyclic group; and Y is adivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms.

(8) In the above-mentioned (7), the heterocyclic group represented by R¹and A is an azolyl group, an azolinyl group or an azolidinyl group.

(9) In the above-mentioned (7), the heterocyclic group represented by R¹is an azolyl group, and the heterocyclic group represented by A is anazolyl group, an azolinyl group or an azolidinyl group.

(10) In the above-mentioned (7), R¹ and A are independently a pyrrolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, imidazolinyl,oxazolinyl or thiazolinyl group which may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₁₀ alkyl, C₆₋₁₄aryl, C₁₋₁₀ alkylthio and oxo.

(11) In the above-mentioned (7), R¹ is an azolyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₁₀ alkyl, C₆₋₁₄ aryl and C₁₋₁₀ alkylthio.

(12) In the above-mentioned (11), the azolyl group is an imidazolyl,pyrazolyl, 1,2,4-triazolyl, or 1,2,3-triazolyl group.

(13) In the above-mentioned (7), A is an azolyl, azolinyl or azolidinylgroup which may be substituted by 1 or 2 C₁₋₁₀ alkyl or oxo.

(14) In the above-mentioned (7), A is an imidazolyl, pyrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl, oxazolinyl,thiazolinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or2,4-dioxothiazolidinyl group which may be substituted by a C₁₋₁₀ alkylgroup.

(15) In the above-mentioned (7), B is an optionally substituted phenylgroup.

(16) In the above-mentioned (7), B is a phenyl group which may besubstituted by a halogen atom.

(17) In the above-mentioned (7), Y is a divalent aliphatic hydrocarbongroup having 3 to 5 carbon atoms.

(18) In the above-mentioned (7), Y is —(CH₂)₃—, —(CH₂)₄— or —(CH₂)₅—.

(19) In the formula (I), R¹ is an optionally substituted heterocyclicgroup; A is an optionally substituted hydroxy group; and Y is a divalentaliphatic hydrocarbon group having 1 to 7 carbon atoms.

(20) In the above-mentioned (19), the heterocyclic group represented byR¹ is an azolyl group.

(21) In the above-mentioned (20), the azoyl group is a pyrrolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl group.

(22) In the above-mentioned (19), R¹ is an azolyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₁₀ alkyl, C₆₋₁₄ aryl and C₁₋₁₀ alkylthio.

(23) In the above-mentioned (22), the azolyl group is an imidazolyl,pyrazolyl, 1,2,4-triazolyl or 1,2,3-triazolyl group.

(24) In the above-mentioned (19), A is (i) a hydroxy group, (ii) a C₁₋₁₀alkoxy group, (iii) a C₂₋₁₀ alkenyloxy group, (iv) a C₇₋₁₀ aralkyloxygroup, (v) a C₂₋₁₃ acyloxy group, (vi) a C₆₋₁₄ aryloxy group which maybe substituted by 1 or 2 halogen or C₁₋₄ alkoxy, or (vii) C₁₋₁₀alkylsulfonyloxy group, and more preferably a hydroxy group.

(25) In the above-mentioned (19), B is an optionally substituted phenylgroup, and more preferably a phenyl group which may be substituted by ahalogen.

(26) In the above-mentioned (19), Y is a divalent aliphatic hydrocarbongroup having 3 to 5 carbon atoms, and more preferably —(CH₂)₃—, —(CH₂)4—or —(CH₂)₅—.

(27) In the formula (I),4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol or itssalt, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol orits salt,4-(4-chlorophenyl)-5-[3-(1-imidazolyl)propyl]-2-(2-methyl-1-imidazolyl)oxazoleor its salt,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanol or itssalt, or4-(4-chlorophenyl)-5-[4-(1-imidazolyl)butyl]-2-(2-methyl-1-imidazolyl)oxazoleor its salt.

As the salts of compounds (I) of the present invention, preferred arepharmaceutically acceptable salts thereof, which include, for example,salts with inorganic bases, salts with organic bases, salts withinorganic acids, salts with organic acids and salts with basic or acidicamino acids. Preferred examples of the salts with inorganic basesinclude alkali metal salts such as sodium salts and potassium salts;alkaline earth metal salts such as calcium salts and magnesium salts;and also aluminum salts and ammonium salts. Preferred examples of thesalts with organic bases include salts with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine or N,N′-dibenzylethylenediamine.Preferred examples of the salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid. Preferred examples of the salts with organic acidsinclude salts with formic acid, acetic acid, trifluoroacetic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid. Preferred examples of the salts with basic aminoacids include salts with arginine, lysine or ornithine; and preferredexamples of the salts with acidic amino acids include salts withaspartic acid or glutamic acid. Of those salts, the most preferred aresodium salts and potassium salts.

The compounds (I) or their salts of the present invention may also be inthe form of hydrates thereof.

The compounds (I) or their pharmaceutically acceptable salts of thepresent invention (hereinafter referred to as the compounds of thepresent invention) have a blood sugar lowering effect and an insulinsecretion-promoting effect.

The compounds of the present invention can be used, either directly orafter having been mixed with any of per-se known, pharmaceuticallyacceptable carriers, excipients, vehicles and others, as insulinsecretion-promoting agents, agents for diabetes, agents forarteriosclerosis, antihyperlipemia, antihypertensive agents, and agentsfor diabetic complications (e.g., nephropathy, retinopathy, neuropathy),which are applicable to mammals (e.g., humans, mice, rats, rabbits,dogs, cats, bovines, horses, pigs, monkeys).

The compounds of the present invention are of low toxicity. For example,when the compound as obtained in Example 36, as described hereinafter,was orally administered to mice in an amount of 1 g/kg/day, there was nomortality at 5 days.

The compounds of the present invention are orally administered in anyform of, for example, tablets, capsules (including soft capsules andmicrocapsules), powders and granules. As the case may be, however, theymay also be parenterally administered for example, as injections,suppositories or pellets. The dose of the compounds of the presentinvention varies depending on the objects to which they areadministered, the administration routes to be employed, and theconditions to which they are directed to. For example, when they areorally administered to adults, the dose thereof may be desirably from 1to 500 mg/kg/day, preferably from 10 to 150 mg/kg/day, and it may beadministered by dividing into 1 to 3 portions.

The pharmaceutical composition of the present invention can be producedby blending the compound of the invention with pharmaceuticallyacceptable carriers. The pharmaceutical composition may be producedaccording to any conventional means that are known in the field offormulations. The pharmaceutical composition may be in any form of solidpreparations such as tablets, capsules, granules or powders, or liquidpreparations such as syrups or injections. These can be administered tomammals such as those mentioned hereinabove, either orally orparenterally.

The pharmaceutical composition of the present invention can be used ininsulin secretion-promoting agents, agents for diabetes, agents forarteriosclerosis, antihyperlipemia, antihypertensive agents, and agentsfor diabetic complications (e.g., nephropathy, retinopathy, neuropathy),and is used especially preferably in insulin secretion-promoting agentsand agents for diabetes.

And the compound (I) of the present invention can be given, to the sameobject, agents for diabetes, agents for diabetic complications,antihyperlipemia or antihypertensive agents at the same time or timelag.

Examples of the agents for diabetes are insulin sensitivity-increasingagents (e.g. pioglitazone, troglitazone, BRL-49653, etc.), α-glucosidaseinhibitor (e.g. voglibose, acarbose, miglitol, etc.) and so on. Examplesof the agents for diabetic complications are aldose reductase inhibitor(e.g. tolrestat, epalrestat, zenarestat, etc.) and so on. Examples ofthe antihyperlipemia are statins such as cholesterol-biosynthesisinhibitor (e.g. pravastatin, simvastatin, lovastatin, cerivastatin,etc.), squalene synthetase inhibitor or fibrates having triglyceridelowering effect (e.g. bezafibrate, etc.). Examples of theantihypertensive agents are angiotensin converting enzyme inhibitor(e.g. captopril, enalapril, delapril, etc.), angiotensin II antagonist(e.g. losartan, candesartan, cilexetil, etc.) and so on.

The pharmaceutically acceptable carriers include various conventional,organic or inorganic carrier substances that are commonly used forformulation matter. For example, for solid preparations, employablecarriers are excipients, lubricants, binders and disintegrators; and forliquid preparations, employable carriers are solvents, dissolution aids,suspending agents, isotonizing agents, buffers and analgesics. Ifdesired, further employable carriers are any other pharmaceuticaladditives such as preservatives, antioxidants, colorants and sweeteners.

Preferred examples of excipients include lactose, white sugar,D-mannitol, starch, crystalline cellulose and light silicic acidanhydride.

Preferred examples of lubricants include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferred examples of binders include crystalline cellulose, whitesugar, D-mannitol, trehalose, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose and polyvinyl pyrrolidone.

Preferred examples of disintegrators include starch, carboxymethylcellulose, calcium carboxymethyl cellulose, sodium cross-carmellose andsodium carboxymethyl starch.

Preferred examples of solvents are water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil and tricaprylin.

Preferred examples of dissolution aids include polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate andsodium citrate.

Preferred examples of suspending agents include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride and glycerolmonostearate; and also hydrophilic polymers such as polyvinyl alcohol,polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylcellulose.

Preferred examples of isotonizing agents include sodium chloride,glycerin and D-mannitol.

Preferred examples of buffers include those of phosphates, acetates,carbonates or citrates.

A preferred example of analgesics is benzyl alcohol.

Preferred examples of preservatives include parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferred examples of antioxidants include sulfites, and ascorbic acid.

The compounds (I) of the present invention can be produced by per-seknown methods. For example, the compounds (I) of the invention can beproduced by the methods mentioned hereinafter or according to these, orby the methods described in EP-92239 and JP59-190979 or according tothose methods.

In the formula (I), a compound represented by the formula (I-a):

wherein R^(1a) is a halogen atom, and the other symbols are of the samemeanings as defined above, or a salt thereof can be produced by reactinga compound represented by the formula:

wherein all symbols are of the same meanings as defined above, or a saltthereof with a halogenating agent, and a compound represented by theformula (I-b):

wherein R^(1b) is an optionally substituted heterocyclic group, anoptionally substituted hydroxy group, an optionally substituted thiolgroup or an optionally substituted amino group, corresponding to R¹, andthe other symbols are of the same meanings as defined above, or a saltthereof can be produced by reacting a compound (I-a) or a salt thereofwith a compound represented by the formula:

R^(1b)—H

wherein all symbols are of the same meanings as defined above, or a saltthereof.

wherein R² represents an alkyl group having 1 to 5 carbon atoms; Xrepresents a halogen atom; and the others are of the same meanings asmentioned above.

The alkyl group having 1 to 5 carbon atoms, represented by R² mayinclude those having 1 to 5 carbon atoms of the examples of the alkylgroup as referred to herein above for the substituent for theheterocyclic group of R¹ or A.

The halogen atom represented by X includes, for example, chlorine,fluorine and bromine.

Compounds (I-1) which correspond to compounds (I) where R¹ is a halogenatom and A is an esterified carboxyl group, can be produced, forexample, by halogenation of compounds (II). This reaction may beconducted generally in the presence of a halogenating agent in a solventthat does not have any influence on the reaction. If desired, an excessamount of such a halogenating agent can be used for the solvent toeffect the reaction.

The halogenating agent includes, for example, phosphorus oxychloride,phosphorus trichloride, phosphorus pentachloride, thionyl chloride andphosphorus tribromide. The amount of the halogenating agent to be usedmay be from 1 to 10 molar equivalents, preferably from 3 to 6 molarequivalents, relative to the compound (II).

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene, toluene and xylene;pyridine; and mixed solvents of these.

The reaction temperature ranges generally from 20 to 180° C., preferablyfrom 50 to 130° C. The reaction time ranges from 0.5 to 20 hours.

The compounds (I-1) thus produced may be isolated and purified throughany ordinary separating and isolating means, for example, throughconcentration, concentration under reduced pressure, solvent extraction,precipitation, recrystallization, phasic transfer, chromatography or thelike.

wherein all symbols are of the same meanings as mentioned above.

Compounds (I-3) which correspond to compounds (I) where A is a carboxylgroup, can be produced, for example, by hydrolysis of compounds (I-2).This reaction may be conducted in any ordinary manner, for example, inthe presence of a base or an acid in an aqueous solvent.

The aqueous solvent may be a mixed solvent comprising water and any ofalcohols (methanol and ethanol), ethers (e.g. tetrahydrofuran anddioxane), dimethylsulfoxide and acetone.

The acid includes, for example, hydrochloric acid, sulfuric acid, aceticacid and hydrobromic acid. The base includes, for example, potassiumcarbonate, sodium carbonate, sodium methoxide, potassium hydroxide,sodium hydroxide and lithium hydroxide. It is desirable that the acid orbase to be used is excess over the compound (I-2) (for example, fromabout 1.2 to about 5 equivalents of the base, or from about 2 to about50 equivalents of the acid).

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from −10° C. to 100° C. The reaction time ranges from 0.1 to20 hours.

The compounds (I-3) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein R³ represents a hydrogen atom or an alkyl group having 1 to 5carbon atoms; Z represents an optionally substituted heterocyclic,hydroxy, thiol or amino group; and the other symbols are of the samemeanings as mentioned above.

The alkyl group having 1 to 5 carbon atoms, represented by R³ mayinclude those having 1 to 5 carbon atoms as referred to hereinabove forthe examples of the alkyl group to be the substituent for theheterocyclic group of R¹ or A.

The optionally substituted heterocyclic, hydroxy, thiol or amino groupwhich are represented by Z may include those as referred to hereinabovefor the optionally substituted heterocyclic, hydroxy, thiol or aminogroup of R¹.

Compounds (I-5) which correspond to compounds (I) where R¹ is anoptionally substituted heterocyclic, hydroxy, thiol or amino group, andA is an optionally esterified carboxy group, can be produced, forexample, by reacting a compound (I-4) with a compound (XI). Thisreaction may be effected generally in the presence of a base in asolvent that does not have any influence on the reaction. Where Z is anoptionally substituted amino group in the compound (XI), an excessamount of said compound (XI) can be used as the solvent.

The solvent that does not have any influence on the reaction includes,for example, alcohols such as methanol and ethanol; ethers such astetrahydrofuran and dioxane; N,N-dimethylformamide, dimethylsulfoxide,acetone, water; and mixed solvents of these.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate,sodium carbonate and sodium hydrogencarbonate; metal hydrides such assodium hydride; sodium ethoxide, and sodium methoxide.

The amount of the compound (XI) to be used may be generally from about 1to about 10 molar equivalents relative to the compound (I-4). Where Z isan optionally substituted amino group in the compound (XI), the amountof the compound (XI) to be used may be generally from about 1 to about50 molar equivalents relative to the compound (I-4).

The reaction temperature ranges generally from 20 to 180° C., preferablyfrom 80 to 140° C. The reaction time ranges from 0.5 to 20 hours.

The compounds (I-5) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein R⁴ represents an alkyl, aralkyl, heteroarylalkyl or acyl group;and the other symbols are of the same meanings as those mentioned above.

The alkyl, aralkyl, heteroarylalkyl or acyl group represented by R⁴,include the alkyl, aralkyl, heteroarylalkyl or acyl group of thealkylthio, aralkylthio, heteroarylalkylthio or acyl group that has beenmentioned hereinabove for the optionally substituted thiol group of R¹.

Compounds (I-6) which correspond to compounds (I) where R¹ is asubstituted thiol group, and A is an optionally esterified carboxygroup, can be produced, for example, by reacting a compound (III) with acompound (XII). This reaction may be conducted in the presence of a basein a solvent that does not have any influence on the reaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate,sodium carbonate and sodium hydrogencarbonate; metal hydrides such assodium hydride; sodium methoxide, and sodium ethoxide.

The solvent that does not have any influence on the reaction includes,for example, ethers such as tetrahydrofuran and dioxane; aromatichydrocarbons such as toluene and xylene; N,N-dimethylformamide,dimethylsulfoxide, acetone, water; and mixed solvents of these.

The amount of the compound (XII) to be used may be from about 1 to about10 molar equivalents relative to the compound (III).

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about 0 to about 100° C. The reaction time ranges from0.1 to 20 hours.

The compounds (I-6) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure,.solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein Y¹ represents a divalent aliphatic hydrocarbon group; and theother symbols are of the same meanings as those mentioned above.

Y¹—CH₂ represents a divalent aliphatic hydrocarbon group represented bythe above-mentioned Y.

Compounds (I-8) which correspond to compounds (I) where A is a hydroxylgroup, can be produced, for example, by reduction of compounds (I-7).This reaction may be conducted in any per-se known manner. Generallyusing a reducing agent, the reduction may be conducted in a solvent thatdoes not have any influence on the reaction.

The reducing agent to be used includes, for example, metal hydrides suchas alkali metal borohydrides (e.g., sodium borohydride, lithiumborohydride), metal-hydrogen complexes (e.g. lithium aluminium hydride),organic tin compounds (e.g. triphenyl tin hydride), diborane, andsubstituted boranes.

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as chloroform, dichloromethane and carbontetrachloride; ethers such as tetrahydrofuran and dioxane; alcohols suchas methanol and ethanol; N,N-dimethylformamide; and mixed solvents ofthese. These solvents may be suitably selected, depending on the type ofthe reducing agent used.

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about 0 to about 100° C. The reaction time ranges from0.1 to 10 hours. The compounds (I-8) thus produced may be isolated andpurified through any ordinary separating and isolating means such asconcentration, concentration under reduced pressure, solvent extraction,precipitation, recrystallization, phasic transfer, chromatography or thelike.

wherein all symbols are of the same meanings as those mentioned above.

Compounds (I-9) which correspond to compounds (I) where A is a formylgroup, can be produced, for example, by oxidation of compounds (I-8).This reaction may be conducted in any per-se known manner. The oxidationmay be effected, for example, with manganese dioxide, chromic acid,dimethylsulfoxide or the like.

Where the oxidation is conducted with dimethylsulfoxide, the reactionmay be conducted in the presence of an electrophilic reagent in asolvent that does not have any influence on the reaction.

The electrophilic reagent includes, for example, acetic anhydride,phosphoric anhydride, oxalyl chloride, dicyclohexylcarbodiimide andchlorine. The amount of the electrophilic reagent to be used may begenerally an equimolar amount relative to dimethylsulfoxide.

The solvent that does not have any influence on the reaction includes,for example, halogenated hydrocarbons such as chloroform anddichloromethane; and aromatic hydrocarbons such as benzene, and toluene.

The amount of dimethylsulfoxide to be used may be from 1 to 5 molarequivalents, preferably from 1 to 2 molar equivalents, relative to thecompound (I-8).

The reaction temperature ranges generally from −20° C. to 100° C.,preferably from about 0 to about 60° C. The reaction time ranges from0.5 to 20 hours.

The compounds (I-9) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer chromatography or the like.

wherein all symbols are of the same meanings as -those mentioned above.

Compounds (I-10) which correspond to compounds (I) where A is asubstituted hydroxy group, can be produced, for example, by acylation ofcompounds (I-8). This reaction may be conducted in any per-se knownmanner. The acylation may be effected, for example, according to amethod of directly condensing the compound (I-8) with a carboxylic acidderivative (R⁴CO₂H), using a dehydrating agent (e.g.,dicyclohexylcarbodiimide), or according to a method of suitably reactingthe compound (I-8) with a reactive derivative of such a carboxylic acidderivative (R⁴CO₂H). The reactive derivative of a carboxylic acidderivative (R⁴CO₂H) includes, for example, acid anhydrides, acid halides(e.g., acid chlorides, acid bromides), imidazolides, and mixed acidanhydrides (e.g., anhydrides with methyl carbonate, ethyl carbonate orisobutyl carbonate).

Of these, the most simple method is to use such an acid chloride or acidanhydride, in which the intended reaction is conducted in the presenceof a base in a solvent that does not have any influence on the reaction.

The base includes, for example, triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate andsodium carbonate.

The solvent that does not have any influence on the reaction includes,for example, halogenated hydrocarbons such as chloroform anddichloromethane; aromatic hydrocarbons such as benzene and toluene;ethyl acetate; and tetrahydrofuran.

The amount of the acid chloride or acid anhydride to be used may be fromabout 1 to about 5 molar equivalents relative to the compound (I-8).

The reaction temperature ranges from about −30° C. to about 100° C. Thereaction time ranges from 0.5 to 20 hours.

The compounds (I-10) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein E represents a halogen atom or OSO₂R⁴; Z¹ represents anoptionally substituted heterocyclic or hydroxy group; and the othersymbols are of the same meanings as those mentioned above.

The halogen atom represented by E includes, for example, chlorine,fluorine and bromine atoms.

The optionally substituted heterocyclic or hydroxy group represented byZ¹ may include the examples of the optionally substituted heterocyclicor hydroxy group as referred to hereinabove for R¹.

Compounds (I-11) which correspond to the compounds (I) where A is anoptionally substituted heterocyclic or hydroxy group, can be produced,for example, by condensation of a compound (IV or I-20) with a compound(XIII). This reaction may be conducted in any ordinary manner, in thepresence of a base in a solvent that does not have any influence on thereaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate and potassiumcarbonate; amines such as pyridine, triethylamine andN,N-dimethylaniline; metal hydrides such as potassium hydride and sodiumhydride; sodium methoxide, sodium ethoxide, and potassium t-butoxide.The amount of the base to be used may be preferably from 1 to 5 molarequivalents relative to the compound (IV or I-20).

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as tetrahydrofuran and dioxane; ketones such as acetone and2-butanone; halogenated hydrocarbons such as chloroform anddichloromethane; N,N-dimethylformamide, dimethylsulfoxide; and mixedsolvents of these.

The reaction temperature ranges generally from −50° C. to 150° C.,preferably from about −10° C. to about 100° C. The reaction time rangesfrom 0.5 to 20 hours.

The compounds (I-11) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein all symbols are of the same meanings as those mentioned above.

Compounds (I-11) which correspond to the compounds (I) where A is anoptionally substituted heterocyclic or hydroxy group, can be produced,for example, by condensation of a compound (I-8) with a compound (XIII).This reaction may be conducted in any ordinary manner, in the presenceof an organic phosphorus compound and an electrophilic reagent in asolvent that does not have any influence on the reaction.

The organic phosphorus compound includes, for example,triphenylphosphine and tributylphosphine. The electrophilic reagentincludes, for example, diethyl azodicarboxylate, diisopropylazodicarboxylate and azodicarbonylpiperazine. The amount of the organicphosphorus compound and that of the electrophilic reagent may bepreferably from 1 to 5 molar equivalents each, relative to the compound(I-8).

The solvent that does not have any influence on the reaction includes,for example, ethers such as diethyl ether, tetrahydrofuran and dioxane;halogenated hydrocarbons such as chloroform and dichloromethane;aromatic hydrocarbons such as benzene, toluene and xylene;N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.

The reaction temperature ranges generally from −50° C. to 150° C.,preferably from about −10° C. to about 100° C. The reaction time rangesfrom 0.5 to 20 hours.

The compounds (I-11) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein all symbols are of the same meanings as those mentioned above.

Compounds (I-12) which correspond to the compounds (I) where A is anamidated carboxy group, can be produced, for example, by reacting acompound (I-7) with a compound (XIV).

Where R³ is an alkyl group having 1 to 5 carbon atoms in the compound(I-7), the reaction may be conducted in the presence of a solvent thatdoes not have any influence on the reaction or in the presence of nosolvent.

The solvent that does not have any influence on the reaction includes,for example, alcohols such as methanol and ethanol; aromatichydrocarbons such as toluene and xylene; pyridine,N,N-dimethylformamide, and dimethylsulfoxide.

The amount of the compound (XIV) to be used is preferably an excess oneover the compound (I-7).

The reaction temperature ranges from 20 to 200° C., and the reactiontime ranges from 0.1 to 20 hours.

Where R³ is a hydrogen atom in the compound (I-7), the reaction may beconducted according to a method of directly condensing the compound(I-7) with the compound (XIV) in the presence of a dehydrating agent(e.g., dicyclohexylcarbodiimide), or a method of suitably reacting areactive derivative of the compound (I-7) with the compound (XIV). Inthis reaction, the reactive derivative of the compound (I-7) includes,for example, acid anhydrides, acid halides (e.g., acid chlorides, acidbromides), imidazolides, and mixed acid anhydrides (e.g., anhydrideswith methyl carbonate, ethyl carbonate or isobutyl carbonate).

Of these, the most simple method is to use such an acid halide or mixedacid anhydride.

For example, when an acid halide is used, the reaction may be conductedin the presence of a base in a solvent that does not have any influenceon the reaction.

The base includes, for example, triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate, andsodium carbonate.

The solvent that does not have any influence on the reaction includes,for example, halogenated hydrocarbons such as chloroform anddichloromethane; aromatic hydrocarbons such as benzene and toluene;ethyl acetate, tetrahydrofuran, water; and mixed solvents of these.

The amount of the compound (XIV) to be used may be from about 1 to about1.5 molar equivalents relative to the compound (I-7).

The reaction temperature ranges from about −30° C. to about 100° C. Thereaction time ranges from 0.5 to 20 hours.

On the other hand, where a mixed acid anhydride is used, the compound(I-7) is first reacted with a chlorocarbonate (e.g., methylchlorocarbonate, ethyl chlorocarbonate, or isobutyl chlorocarbonate) inthe presence of a base (e.g., triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate,sodium carbonate), and then reacted with the compound (XIV). The amountof the compound (XIV) to be used may be from about 1 to about 1.5 molarequivalents relative to the compound (I-7).

This reaction may be conducted in a solvent that does not have anyinfluence on the reaction. Such an inert solvent includes, for example,halogenated hydrocarbons such as chloroform and dichloromethane;aromatic hydrocarbons such as benzene and toluene; ethyl acetate,tetrahydrofuran, water; and mixed solvents of these.

The reaction temperature ranges from about −30° C. to about 50° C., andthe reaction time ranges from 0.5 to 20 hours.

The compounds (I-12) thus produced may be isolated and purified throughany ordinary separating and isolating means, for example, throughconcentration, concentration under reduced pressure, solvent extraction,precipitation, recrystallization, transsolvation, chromatography or thelike.

wherein n represents 2 or 3; and the other symbols are of the samemeanings as those mentioned above.

Compounds (I-14) which correspond to the compounds (I) where A is aheterocyclic group, can be produced, for example, through cyclization ofa compound (I-13).

This reaction may be conducted in the presence of a base in a solventthat does not have any influence on the reaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate and potassiumcarbonate; amines such as pyridine, triethylamine andN,N-dimethylaniline; metal hydrides such as potassium hydride and sodiumhydride; sodium methoxide, sodium ethoxide, and potassium t-butoxide.The amount of the base to be used may be preferably from 1 to 5 molarequivalents relative to the compound (I-13).

The solvent that does not have any influence on the reaction includes,for examples aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as tetrahydrofuran and dioxane; ketones such as acetone and2-butanone; halogenated hydrocarbons such as chloroform anddichloromethane; N,N-dimethylformamide, dimethylsulfoxide; and mixedsolvents of these.

The reaction temperature ranges generally from −50° C. to 150° C.,preferably from about −10° C. to about 100° C. The reaction time rangesfrom 0.5 to 20 hours.

The compounds (I-14) thus produced may be isolated and purified throughany ordinary separating and isolating means, for example, throughconcentration, concentration under reduced pressure, solvent extraction,precipitation, recrystallization, transsolvation, chromatography or thelike.

wherein R⁷ represents an alkyl, aralkyl, aryl or heteroarylalkyl group;and the other symbols are of the same meanings as those mentioned above.

The alkyl, aralkyl, aryl or heteroarylalkyl group to represented by R⁷,include the examples of the alkyl, aralkyl, aryl or heteroarylalkylmoiety of the esterified carboxy group, or that is, the alkoxycarbonyl,aralkyloxycarbonyl, aryloxycarbonyl or heteroarylalkyloxycarbonyl group,that have been mentioned hereinabove for the substituent for R¹ or A.

Compounds (I-15) which correspond to the compounds (I) where A is anesterified carboxy group, can be produced, for example, by reacting acompound (I-3) with a compound (XV). This reaction may be conducted inany ordinary manner, in the presence of a base in a solvent that doesnot have any influence on the reaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, lithium hydroxide, sodiumhydrogencarbonate, potassium carbonate and sodium carbonate; metalhydrides such as sodium hydride; sodium methoxide, and sodium ethoxide.

The solvent that does not have any influence on the reaction includes,for example, ethers such as tetrahydrofuran and dioxane; ketones such asacetone and 2-butanone; N,N-dimethylformamide, dimethylsulfoxide; andmixed solvents of these.

The amount of the compound (XV) to be used may be preferably from about1 to about 10 molar equivalents relative to the compound (I-3).

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about 0° C. to about 100° C. The reaction time rangesfrom 0.5 to 20 hours.

The compounds (I-15) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein all symbols are of the same meanings as those mentioned above.

The compound (I-16) can be produced by dehydroxylation of the compound(XVI). In this method, the compound (XVI) is directly reduced by silane,or the hydroxy group on the compound (XVI) is halogenated and furtherreduced. The reduction with silane is promoted by reaction with thecompound (XVI) and triethylsilane or diethylsilane in trifluoro aceticacid. The halogenating agent includes, for example, thionyl chloride andphosphorus tribromide. For the reducing agent, metals such as iron, zincare preferably used in hydrochloric acid or acetic acid.

The compounds (I-16) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extration, precipitation,recrystallization, phasic transfer, chromatography or the like.

The starting compounds(XVI) can be produced by the following Method N.

wherein all symbols are of the same meanings as those mentioned above.

In this method, the compound(XIX) can be produced by condensing thecompound(XVII) and the compound(XVIII). This condensing reaction is thesame manner as producing the compound(VII) by condensing the compound(V)and the compound(VI) as described in the Method R. Further, thecompound(XX) can be produced by halogenating the compound(XIX). Thishalogenating reaction is the same manner as the halogenating reaction ofthe compound(II) as described in the Method A. The compound(XXI) can beproduced by reacting with thus-obtained compound(XX) and thecompound(XI). This reaction is conducted in the same manner as producingthe compound(I-5) by reacting with the compound(I-4) and thecompound(XI). Further, the compound(XVI) can be produced by reducing thecompound(XXI). The reducting reaction is conducted in the same manner asthe reacting reaction as described in the Method E.

wherein all symbols are of the same meanings as those mentioned above.

The compound(I-17) wherein A is a heterocyclic group in the compound(I)can be produced by reacting with the compound(I-9).and thecompound(XXII). This reaction may be effected in any ordinary manner,for example, in the presence of a base or an acid in a solvent that doesnot have any influence on the reaction. The acid used in this reactionincludes, for example, hydrochloric acid, sulfuric acid, phosphoricacid, acetic acid and p-toluenesulfonic acid. The base used in thisreaction includes, for example, sodium acetate and p-toluenesulfonylpyridine.

The amount of the acid or the base to be used may be from about 0.1 to 2molar equivalents relative to the compound(I-9).

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene, toluene;tetrahydrofuran; acetic acid.

The reaction temperature generally ranges from about −20 to 200° C.,preferably from about 0 to 150° C. The reaction time ranges from about0.5 to 20 hours.

The compounds (I-17) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extration, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein all symbols are of the same meanings as those mentioned above.

The compound(I-18) wherein A is a heterocyclic group in the compound(I)can be produced by reacting with the compound(XXIV) and thecompound(XXV). This reaction may be conducted in any ordinary manner ina solvent that does not have any influence on the reaction. The solventthat does not have any influence on the reaction includes, for example,alcohols such as methanol, ethanol, propanol, isopropanol; aromatichydrocarbons such as benzene, toluene; tetrahydrofuran;N,N-dimethylformamide; pyridine; acetic acid.

The reaction temperature generally ranges from about −20 to 200° C.,preferably about 0 to 150° C. The reaction time ranges from about 0.5 to20 hours.

The compounds (I-18) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extration, precipitation,recrystallization, phasic transfer, chromatography or the like.

wherein all symbols are of the same meanings as those mentioned above.

The compound(XXIV) can be produced by dehydration of the compound(I-19).This reaction may be conducted in any ordinary manner in a solvent thatdoes not have any influences on the reaction. The dehydrating agentincludes, for example, sulfuric acid, acetic anhydride, phosphoruspentaoxide, phosphorus oxychloride. This solvent that does not have anyinfluences on the reaction includes, for example, alcohols such asmethanol, ethanol, propanol, isopropanol; aromatic hydrocarbons such asbenzene, toluene; tetrahydrofuran; N,N-dimethylformamide.

The reaction temperature generally ranges from about −20 to 200° C.,preferably 0 to 150° C. The reaction time ranges from about 0.5 to 20hours.

The compounds (XXIV) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extration, precipitation,recrystallization, phasic transfer, chromatography or the like.

The starting compounds (II), (III) and (IV) to be used for theproduction of the compounds (I) of the invention can be produced by anyper-se known methods. For example, these starting compounds can beproduced by the methods mentioned hereinafter or according to these, orby the methods described in EP-92239 and JP59-190976 or according tothose methods.

The starting compounds (II) for the Method A can be produced, forexample, by the following method R.

wherein B¹ represents an optionally substituted phenyl group; and theother symbols are of the same meanings as those mentioned above.

The substituent for the optionally substituted phenyl group representedby B¹ includes, for example, an alkyl group having 1 to 4 carbon atoms(e.g., methyl), a halogen atom (e.g., chlorine), and a nitro group.

In this process, a compound (V) is first condensed with a compound (VI)to obtain a compound (VII). This reaction may be conducted in anyordinary manner, in the presence of a Lewis acid and in the presence ofa solvent that does not have any influence on the reaction or in thepresence of no solvent.

The Lewis acid includes, for example, aluminium chloride, titaniumtetrachloride, tin tetrachloride, and boron trifluoride. The amount ofthe Lewis acid to be used may be preferably from 1 to 5 molarequivalents relative to the compound (V).

The solvent that does not any influence on the reaction includes, forexample, halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane and carbon tetrachloride; carbon disulfide; and mixedsolvents of these.

The amount of the compound (VI) to be used may be from 1 to 5 molarequivalents, preferably from 1 to 3 molar equivalents, relative to thecompound (V).

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about −10° C. to about 80° C. The reaction time rangesfrom 0.5 to 20 hours.

Next, the compound (VII) is halogenated to obtain a compound (VIII).This reaction may be conducted in any ordinary manner, generally in thepresence of a halogenating agent in a solvent that does not have anyinfluence on the reaction.

The halogenating agent includes, for example, chlorine and bromine. Theamount of the halogenating agent to be used may be preferably from 1 to1.5 molar equivalents relative to the compound (VII).

The solvent that does not have any influence on the reaction includes,for example, ethers such as diethyl ether, tetrahydrofuran and dioxane;halogenated hydrocarbons such as dichloromethane and chloroform; aceticacid; and mixed solvents of these.

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about −10° C. to about 80° C. The reaction time rangesfrom 0.5 to 20 hours.

Next, the thus-obtained compound (VIII) is suitably reacted with a saltof an organic acid in the presence of a solvent that does not have anyinfluence on the reaction, to obtain a compound (IX).

The salt of an organic acid includes, for example, sodium formate,potassium formate, and sodium acetate. The amount of the salt may befrom 1 to 20 molar equivalents, preferably from about 2 to about 10molar equivalents, relative to the compound (VIII).

The solvent that does not have any influence on the reaction includes,for example, alcohols such as methanol and ethanol.

The reaction temperature ranges generally from 0 to 150° C., preferablyfrom about 30 to about 100° C. The reaction time ranges from 1 to 50hours.

Next, the resulting compound (IX) is reacted with a chlorocarbonate toobtain a compound (X). This reaction may be conducted in any ordinarymanner, in the presence of a base in a solvent that does not have anyinfluence on the reaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate and potassiumcarbonate; and amines such as pyridine, triethylamine andN,N-dimethylaniline. The amount of the base to be used may be preferablyfrom 2 to 5 molar equivalents relative to the compound (IX).

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbonssuch as chloroform and dichloromethane; N,N-dimethylformamide,dimethylsulfoxide; and mixed solvents of these.

The reaction temperature ranges generally from −50° C. to 150° C.,preferably from about −30° C. to about 50° C. The reaction time rangesfrom 0.5 to 20 hours.

Next, the compound (X) is reacted with ammonia or its salt to obtain theintended compound (II). This reaction may be conducted generally in thepresence of a solvent that does not have any influence on the reaction.

The ammonia or its salt includes, for example, ammonia gas, and ammoniumacetate. For example, when such an ammonium salt is used, its amount maybe from 1 to 20 molar equivalents relative to the compound (X).

The solvent that does not have any influence on the reaction includes,for example, ethers such as tetrahydrofuran and dioxane; acetic acid;and mixed solvents of these.

The reaction temperature ranges generally from 0 to 150° C., preferablyfrom about 50 to about 120° C. The reaction temperature ranges from 0.5to 20 hours.

The compounds (II) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

The starting compounds (III) for the Method D can be produced, forexample, by the following method S.

wherein all symbols are of the same meanings as those mentioned above.

The compounds (III) can be produced by reacting a compound (I-1) withthiourea, thioacetic acid or its salt, in the presence of a base in asuitable solvent that does not have any influence on the reaction.

The base includes, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, lithium hydroxide, sodiumhydrogencarbonate, and potassium carbonate.

The solvent that does not have any influence on the reaction includes,for example, ethers such as tetrahydrofuran and dioxane;N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.

The amount of thiourea, thioacetic acid or its salt to be used may befrom 1 to 20 molar equivalents, preferably from about 2 to about 10molar equivalents, relative to the compound (I-1).

The reaction temperature ranges generally from 0 to 150° C., preferablyfrom about 50 to about 120° C. The reaction time ranges from 0.1 to 20hours.

The compounds (III) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

The starting compounds (IV) for the Method H can be produced, forexample, by the following method T.

wherein all symbols are of the same meanings as those mentioned above.

The compound (IV), wherein E is halogen, can be produced by reacting acompound (I-8) with a halogenating agent, and the compound (IV), whereinE is OSO₂R⁴, can be produced by reacting a compound (I-8) with asulfonylating agent.

Where a halogenating agent is used, it is preferably thionyl chloride,phosphorus tribromide or the like. In this case, produced are thecompounds (IV) where E is chlorine or bromine. The amount of thehalogenating agent to be used may be from about 1 to about 20 molarequivalents relative to the compound (I-8).

The reaction may be effected generally in a solvent that does not haveany influence on the reaction (e.g., benzene, toluene, chloroform,dichloromethane). If desired, an excess amount of the halogenating agentmay be used for the solvent.

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about 10 to about 100° C. The reaction time ranges 0.1to 20 hours.

Where a sulfonylating agent is used, it is preferably mesyl chloride,tosyl chloride, benzenesulfonyl chloride or the like. In this case,produced are the compounds (I-20) where E is a mesyloxy, tosyloxy orbenzenesulfonyloxy group, respectively.

The reaction may be conducted generally in the presence of a solventthat does not have any influence on the reaction, preferably in thepresence of a suitable base.

The solvent that does not have any influence on the reaction includes,for example, aromatic hydrocarbons such as benzene and toluene;halogenated hydrocarbons such as chloroform and dichloromethane; ethylacetate, and tetrahydrofuran.

The base includes, for example, triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate, andsodium carbonate.

The amount of the sulfonylating agent and that of the base to be usedmay be from about 1 to about 1.5 molar equivalents each, relative to thecompound (I-8).

The reaction temperature ranges generally from −20° C. to 150° C.,preferably from about 10 to about 100° C. The reaction time ranges from0.1 to 20 hours.

The compounds (IV) thus produced may be isolated and purified throughany ordinary separating and isolating means such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization, phasic transfer, chromatography or the like.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the present invention is described in more detail hereinunder, withreference to the following test example, reference examples, examplesand formulation examples, which, however, are not intended to restrictthe scope of the invention. In the following reference examples andexamples, % is by weight unless otherwise specifically indicated.

Experimental Example 1 Test for Blood Sugar Depression in Mice

After being fasted for 20 hours, 9- to 12-week-old, male KKA^(y) mice(five mice in each group) were orally given the test compound at a doseof 30 mg/kg/10 ml through a stomach tube. Control mice were orally given5% gum arabic solution. Blood samples (70 μl) were obtained from orbitalvenous plexus through capillary tube before and 60 and 120 minutes afterthe administration of the test compound. Blood glucose was determinedaccording to a glucose oxidase method using a commercial kit (Iatrochem,GIU(A), latron Labs. Inc.). Blood glucose level at 60 or 120 minutes ofthe test groups was compared with that of control group, and was shownas blood glucose depression (%) (Table 1).

TABLE 1 Test Compound Degree of Blood Glucose Depression (%) (ExampleNumber) After 60 minutes After 120 minutes 15 22 26 25 38 27 26 32 27 2824 33 31 27 28 32 25 28 34 27 25 36 23 18

As demonstrated in the above table 1, the compounds (I) of the presentinvention have a blood sugar (blood glucose) depressing effect and areuseful in agents or diabetes.

Experimental Example 2 Insulinotropic effect on MIN6 cells

MIN6 cells established from mouse beta cell tumor were cultured in DMEMsupplemented with 15% fetal bovine serum on 12-well plate at 37° C. in5% CO₂, and were used at the stage of subconfluency. Cells were washedtwice with PBS and incubated in Krebs-Ringer HEPES(KRH) containing with0.1 mM glucose for 30 minutes. Then they were incubated in KRHcontaining with 12.5 mM glucose and 0.1% DMSO (control) or compound (10μM) for 2 hours. Medium was collected and insulin concentration wasmeasured using a commercial radioimmunoassay kit (Amarsham Inc.). Theplate was washed once with PBS and cellular protein content wasdetermined by the method of Lowrey et al.(J. Biol. Chem. 193, 265-275,1951). Insulinotropic activity of the compound was indicated aspercentage of control (Table 2).

TABLE 2 Test Compound Insulin secretion- (Example Number) promotingeffect (%) 36 272 65 397 72 303 83 359 89 385

As demonstrated in the above Table 2, the compounds (I) of the presentinvention have insulin secretion-promoting effect and are useful inagents for diabetes.

Reference Example 1

Bromine (46.5 g) was added dropwise to a dichloromethane (400 ml)solution of methyl 4-(4-chlorobenzoyl)butyrate (70.0 g). After stirringfor 15 minutes, the reaction mixture was washed with water, dried(MgSO₄), and concentrated to obtain methyl4-bromo-4-(chlorobenzoyl)butyrate (89.5 g, 96%) as an oily substance.NMR (δ ppm in CDCl₃): 2.3-2.7(4 H,m), 3.71(3H,s), 5.33(1H,dd,J=8&5.5Hz), 7.48(2H,d,J=8.5 Hz), 7.98(2H,d,J=8.5 Hz).

Reference Example 2

A mixture of methyl 4-bromo-4-(chlorobenzoyl)butyrate (89.5 g), sodiumformate (76.2 g) and methanol (400 ml) was stirred under reflux for 12hours. The reaction mixture was concentrated, and water was added to theresulting residue and then extracted with ethyl acetate. The ethylacetate layer was washed with water, and dried (MgSO₄). The solvent wasevaporated to give methyl 4-(chlorobenzoyl)-4-hydroxybutyrate (72.0 g,100%) as an oily substance. This oily substance (72.0 g) was dissolvedin tetrahydrofuran (400 ml), pyridine (22.2 g) was added thereto, andthereafter phenyl chlorocarbonate (43.8 g) was dropwise added theretowith cooling with ice. After the reaction mixture was stirred at roomtemperature for 1 hour, water was added to the reaction mixture and thenextracted with ethyl acetate. The ethyl acetate layer was washed with 2Nhydrochloric acid and then with water, and dried (MgSO₄). The solventwas evaporated, and the crystals thus precipitated were collected byfiltration to obtain methyl4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g, 58%). This wasrecrystallized from methanol to give colorless prisms. mp 97-98° C.

Reference Example 3

A mixture of methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate(61.2 g), ammonium acetate (62.2 g) and acetic acid (300 ml) was stirredunder reflux for 1.5 hours. The reaction mixture was concentrated, waterwas added to the resulting residue, and the crystals thus precipitatedwere collected by filtration. These were recrystallized from methanol togive colorless needles of methyl3-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]propionate (36.6 g, 79%).m.p. 147-148° C.

Reference Example 4

A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate(5.72 g), thiourea (4.57 g) and ethanol (70 ml) was stirred under refluxfor 30 minutes. An aqueous solution of 2N sodium hydroxide (40 ml) wasadded to the reaction mixture, and stirred under reflux for anadditional 30 minutes. Water was added to the reaction mixture, whichwas then neutralized with 6N hydrochloric acid. The crystals thusprecipitated were collected by filtration to obtain3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (5.41 g,yield: 96%). This was recrystallized from ethanol to give colorlessneedles. mp 196-197° C.

Reference Example 5

Phosphorus oxychloride(585 mg) was added dropwise into aN,N-dimethylformamide solution (20 ml) of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(840mg) at room temperature. After stirring for 1 hour, the reaction mixturewas poured into ice water, and neutralized with saturated sodiumbicarbonate. The precipitating crystals are collected by filtration togive4-(4-chlorophenyl)-5-(2-cyanoethyl)-2-(2-methyl-1-imidazolyl)oxazole(650mg, 82%). This was recrystallized with acetone-isopropyl ether to givecolorless prisms. mp 163-164° C.

Reference Example 6

Adipic acid monomethyl ester chloride (17.9 g) was added dropwise into amixture of chlorobenzene(33.8 g) and aluminum chloride anhydrous(26.7 g)with cooling with ice. After stirring for 2 hours, the reaction mixturewas poured into ice water, and extracted with ethyl acetate. The ethylacetate layer was washed with water, and dried (MgSO₄). The solvent wasevaporated to give methyl 5-(4-chlorobenzoyl)pentanoate. This wasdissolved into dichloromethane(100 ml), thereto bromine(16.0 g) wasadded dropwise. The reaction mixture was washed with water and then withsodium hydrogensulfite. The dichloromethane layer was washed with water,and dried (MgSO₄). The solvent was evaporated to give methyl5-bromo-5-(4-chlorobenzoyl)pentanoate(31.7 g, 95%) as an oily substance.

NMR(δ ppm in CDCl₃): 1.6-2.3(4H, m), 2.42(2H, t, J=7 Hz), 3.68(3H, s),5.08(1H, dd, J=8&6.5 Hz), 7.47(2H, d, J=9 Hz), 7.96(2H, d, J=9 Hz).

Reference Example 7

In the same manner as Reference Example 2, methyl5-(4-chlorobenzoyl)-5-phenoxycarbonyloxypentanoate as an oily substance(yield: 67%) was obtained by reacting a reactant which was obtained byreacting methyl 5-bromo-5-(4-chlorobenzoyl)pentanoate with sodiumformate, with phenyl chlorocarbonate.

NMR(δ ppm in CDCl₃): 1.8-2.1(4H, m), 2.40(2H, t, J=7 Hz), 3.67(3H, s),5.82(1H, dd, J=7.5&4.5 Hz), 7.15-7.45(5H, m), 7.48(2H, d, J=9 Hz),7.91(2H, d, J=9 Hz).

Reference Example 8

In the same manner as Reference Example 3, obtained was methyl4-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl)butanoate by reaction ofmethyl 5-(4-chlorobenzoyl)-5-phenoxycarbonyloxypentanoate with ammoniumacetate. This was recrystallized with acetone-isopropyl ether to givecolorless prisms. mp 121-122° C.

Reference Example 9

Titanium tetrachloride(15.5 g) was added dropwise into a mixture of4-(4-chlorophenyl)-4-oxazolin-2-one(4.00 g), ethyl chloroglyoxylate(5.58g) and dichloromethane(30 ml) at room temperature. After stirring for 2hours, the reaction mixture was poured into ice water, and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, anddried(MgSO₄). The solvent was evaporated to give ethyl2-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]-2-oxoacetate ascrystals(5.38 g, 89%). This was recrystallized from ethyl acetate-hexaneto give pale yellow prisms. mp 152-153° C.

Reference Example 10

A mixture of ethyl2-(4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]-2-oxoacetate(2.50 g),phosphorus oxychloride(6.48 g) and pyridine(740 mg) was stirred for 1hour at 120-125° C. The reaction mixture was poured into ice water, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chromatography. From the fractioneluted with ethyl acetate-hexane(1:9, v/v), obtained was ethyl2-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl)-2-oxoacetate(450 mg, 17%).This was recrystallized from ethyl acetate-hexane to give colorlessprisms. mp 98-99° C.

Reference Example 11

Sodium hydride(oil, 60%, 710 mg) was gradually added to a mixture ofethyl 2-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]-2-oxoacetate(4.63 g),2-methylimidazole(1.45 g) and N,N-dimethylformamide(50 ml) at 0° C.After stirring for 1 hour at room temperature, the reaction mixture waspoured into ice water to give ethyl2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(3.12g, 59%). This was recrystallized from ethyl acetate-hexane to givecolorless prisms. mp 126-127° C.

Reference Example 12

Sodium borohydride(95 mg) was added to a tetrahydrofuran(60ml)-2-propanol(30 ml) solution of ethyl2-(4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(2.93g) at 0° C. After stirring for 30 minutes, the reaction mixture waspoured into ice water, and extracted with ethyl acetate. The ethylacetate layer was washed with water, and dried(MgSO₄). The solvent wasevaporated to give ethyl2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-hydroxyacetate(2.20g, 75%). This was recrystallized from acetone-ethyl acetate to givecolorless prisms. mp 197-198° C. (degradation)

Reference Example 13

N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalylchloride(18.8 g) was added dropwise. After stirring for 2 hours at roomtemperature, the reaction mixture was concentrated. The residue wasadded dropwise to a mixture of chlorobenzene(61.0 g) and aluminumchloride anhydrous (36.1 g) under ice water. After stirring for 3 hours,the reaction mixture was poured into 1N-hydrochloric acid, and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, anddried(MgSO₄). The solvent was evaporated to give ethyl6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.3-1.9(6H, m), 2.32(2H, t,J=7.5 Hz), 2.95(2H, t, J=7.5 Hz), 4.13(2H, q, J=7 Hz), 7.44(2H, d, J=8.5Hz), 7.90(2H, d, J=8.5 Hz).

Reference Example 14

In the same manner as Reference Example 13, obtained was ethyl7-(4-chlorobenzoyl)heptanoate as an oily substance(yield: 90%) byreaction of a reactant of suberic acid monoethyl ester and oxalylchloride, with chlorobenzene.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.2-1.9(8H, m), 2.2-2.4(2H,m), 2.93(2H, t, J=7.5 Hz), 4.13(2H, q, J=7 Hz), 7.43(2H, d, J=8.5 Hz),7.90(2H, d, J=8.5 Hz).

Reference Example 15

Bromine(21.1 g) was added dropwise to a dichloromethane solution (200ml) of ethyl 6-(4-chlorobenzoyl)hexanoate (37.3 g) at room temperature.After stirring for 30 minutes, the reaction mixture was washed withsodium hydrogensulfite, saturated sodium bicarbonate and water in turn.The dichloromethane layer was dried(MgSO₄). The solvent was evaporatedto give ethyl 6-bromo-6-(4-chlorobenzoyl)hexanoate(47.6 g, quant.) as anoily substance.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.3-2.3(6H, m), 2.34(2H, t,J=7 Hz), 4.13(2H, q, J=7 Hz), 5.06(1H, t, J=7 Hz), 7.47(2H, d, J=8.5Hz), 7.96(2H, d, J=8.5 Hz).

Reference Example 16

In the same manner as Reference Example 15, obtained was ethyl7-bromo-7-(4-chlorobenzoyl)heptanoate(yield: 79%) as an oily substancethrough reaction of ethyl 7-(4-chlorobenzoyl)heptanoate with bromine.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.2-1.9(8H, m), 2.2-2.4(2H,m), 4.12(2H, q, J=7 Hz), 5.06(1H, t, J=7 Hz), 7.47(2H, d, J=8.5 Hz),7.96(2H, d, J=8.5 Hz).

Reference Example 17

A mixture of ethyl 6-bromo-6-(4-chlorobenzoyl)hexanoate (47.6 g), sodiumformate(44.8 g) and methanol(250 ml) was stirred for 24 hours underreflux. The reaction mixture was concentrated. Water was added to thereaction mixture. This was extracted with ethyl acetate. The ethylacetate layer was washed with water, and dried(MgSO₄). The residueobtained by evaporating the solvent was subjected to silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane(1:4,v/v), obtained was ethyl 6-(4-chlorobenzoyl)-6-hydroxyhexanoate(24.5 g,62%) as an oily substance.

NMR(δ ppm in CDCl₃): 1.23(3H, t, J=7 Hz), 1.3-2.0(6H, m), 2.28(2H, t,J=7 Hz), 3.63(1H, d, J=6.5 Hz), 4.10(2H, q, J=7 Hz), 4.95-5.1(1H, m),7.49(2H, d, J=8.5 Hz), 7.86(2H, d, J=8.5 Hz).

Reference Example 18

In the same manner as Reference Example 17, obtained was ethyl7-(4-chlorobenzoyl)-7-hydroxyheptanoate (yield: 31%) as an oilysubstance by reaction of ethyl 7-bromo-7-(4-chlorobenzoyl)heptanoatewith sodium formate in methanol.

NMR(δ ppm in CDCl₃): 1.24(3H, t, J=7 Hz), 1.3-2.0(8H, m), 2.27(2H, t,J=7.5 Hz), 3.63(1H, d, J=6.5 Hz), 4.11(2H, q, J=7 Hz), 4.95-5.1(1H, m),7.49(2H, d, J=8.5 Hz), 7.87(2H, d, J=8.5 Hz).

Reference Example 19

Phenyl chloroformate (14.1 g) was added dropwise to a mixture of ethyl6-(4-chlorobenzoyl)-6-hydroxyhexanoate (24.5 g), pyridine(7.14 g) andtetrahydrofuran(200 ml) with cooling with ice. After stirring for 3hours at room temperature, the reaction mixture was poured into icewater, and neutrized by 2N-hydrochloric acid. This was extracted withethyl acetate. The ethyl acetate layer was washed with water, anddried(MgSO₄). The solvent was evaporated to give ethyl6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanate(32.3 g, 94%) as an oilysubstance.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.45-2.05(6H, m), 2.32(2H, t,J=7 Hz), 4.12(2H, q, J=7 Hz), 5.79(1H, t, J=6 Hz), 7.1-7.5(7H, m),7.89(2H, d, J=8.5 Hz).

Reference Example 20

In the same manner as Reference Example 19, obtained was ethyl7-(4-chlorobenzoyl)-7-phenoxycarbonyloxyheptanoate (quant.) as an oilysubstance by reaction of ethyl 7-(4-chlorobenzoyl)-7-hydroxyheptanoatewith phenyl chloroformate.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7 Hz), 1.25-2.0(8H, m), 2.29(2H, t,J=7.5 Hz), 4.12(2H, q, J=7 Hz), 5.79(1H, t, J=7 Hz), 7.15-7.45(5H, m),7.48(2H, d, J=8.5 Hz), 7.90(2H, d, J=8.5 Hz).

Reference Example 21

Ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanoate (32.3 g),ammonium acetate(29.7 g) and acetic acid(150 ml) was stirred for 1 hourunder reflux. Water was added to the reaction mixture to give ethyl5-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]pentanoate(17.7 g, 71%).This was recrystallized from acetone-isopropyl ether to give colorlessneedls. mp 143-144° C.

Reference Example 22

In the same manner as Reference Example 21, obtained was ethyl6-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]hexanoate (yield: 87%) byreaction of ethyl 7-(4-chlorobenzoyl)-7-phenoxycarbonyloxyheptanoatewith ammonium acetate.

This was recrystallized with acetone-isopropyl ether to give colorlessprisms mp 113-114° C.

EXAMPLE 1

A mixture of methyl3-[4-(4-chlorophenyl)-2-oxo-4-oxazoline-5-yl]propionate (11.3 g),phosphorus oxychloride (18.6 g) and pyridine (3.2 ml) was stirred at 120to 180° C. for 80 minutes. The reaction mixture was concentrated, andice water was added thereto and then stirred at room temperature for 30minutes. Then, this was extracted with ethyl acetate. The ethyl acetatelayer was washed with water, and dried (MgSO₄). The solvent wasevaporated, and the crystals thus precipitated were collected byfiltration. These were recrystallized from isopropyl ether to givecolorless needles of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.56 g, 71%). m.p.71-72° C.

Example 2

An aqueous solution of 1N sodium hydroxide (34 ml) was dropwise added toan ethanol (50 ml) solution of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.50 g), with coolingwith ice. After stirring for 20 minutes with cooling and then for 30minutes at room temperature, 2N hydrochloric acid was added thereto, andthe crystals thus precipitated were collected by filtration to obtain2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (8.00 g, 99%). Thiswas recrystallized from ethyl acetate to give colorless prisms. mp169-170° C.

Example 3

2-Chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g) was addedto an ethanol solution of sodium ethoxide prepared from sodium (0.35 g)and ethanol (15 ml), and stirred under reflux for 30 minutes. Thesolvent was evaporated, and water was added to the residue, which wasthen acidified with 2N hydrochloric acid. The crystals thus precipitatedwere collected by filtration to obtain4-(4-chlorophenyl)-2-ethoxy-5-oxazolepropionic acid (1.40 g, 95%). Thiswas recrystallized from ethanol to give colorless prisms. mp 148-149° C.

Example 4

Sodium hydride (60% dispersion in oil, 0.60 g) was added to 2-propanol(20 ml), and stirred at room temperature for 10 minutes. To the reactionmixture was added 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid(1.43 g), and stirred under reflux for 30 minutes. Next, water was addedto the resulting reaction mixture, which was then acidified with 2Nhydrochloric acid, and the crystals thus precipitated were collected byfiltration to obtain 4-(4-chlorophenyl)-2-isopropoxy-5-oxazolepropionicacid (1.35 g, 87%). This was recrystallized from isopropyl ether to givecolorless prisms. mp 116-117° C.

Example 5

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), phenol (0.94 g), potassium carbonate (2.10 g) andN,N-dimethylformamide (10 ml) was stirred at 140° C. for 3 hours. Waterwas added to the reaction mixture, which was then acidified with 6Nhydrochloric acid. The crystals thus precipitated were collected byfiltration to obtain 4-(4-chlorophenyl)-2-phenoxy-5-oxazolepropionicacid (1.60 g, 93%). This was recrystallized from ethyl acetate to givecolorless needles. mp 136-137° C.

Example 6

Methyl iodide (0.34 ml) was dropwise added to a mixture of3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (1.42 g),an aqueous solution of 2N sodium hydroxide (5.5 ml) andN,N-dimethylformamide (15 ml), with cooling with ice. After the reactionmixture was stirred for 30 minutes, water was added to the resultingreaction mixture, which was then acidified with 2 N hydrochloric acid.The crystals thus precipitated were collected by filtration to obtain4-(4-chlorophenyl)-2-methylthio-5-oxazolepropionic acid (1.45 g, 97%).This was recrystallized from ethanol to give colorless needles. mp183-184° C.

Example 7

In the same manner as in Example 6, obtained was4-(4-chlorophenyl)-2-isopropylthio-5-oxazolepropionic acid (yield: 80%)by reaction of 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionicacid with isopropyl iodide. This was recrystallized from ethanol to givecolorless prisms. mp 132-133° C.

Example 8

In the same manner as in Example 6, obtained was4-(4-chlorophenyl)-2-(2-pyridylmethylthio)-5-oxazolepropionic acid(yield: 98%) by reaction of3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid with2-(chloromethyl)pyridine. This was recrystallized from ethanol to givecolorless prisms. mp 125-126° C.

Example 9

In the same manner as in Example 6, obtained was4-(4-chlorophenyl)-2-(3-pyridylmethylthio)-5-oxazolepropionic acid(yield: 96%) by reaction of3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid with3-(chloromethyl)pyridine. This was recrystallized from ethanol to givecolorless needles. mp 129-130° C.

Example 10

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), thiophenol (0.54 ml), sodium methoxide-methanol solution (28%, 2.00g) and methanol (15 ml) was stirred under reflux for 16 hours. Water wasadded to the reaction mixture, which was then acidified with 2 Nhydrochloric acid. The crystals thus precipitated were collected byfiltration to obtain 4-(4-chlorophenyl)-2-phenylthio-5-oxazolepropionicacid (1.60 g, 89%). This was recrystallized from methanol to givecolorless needles. mp 156-157° C.

Example 11

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), 4-methylthiophenol (0.68 g), potassium carbonate (2.07 g) andN,N-dimethylformamide (20 ml) was stirred under a nitrogen atmosphere at100° C. for 40 minutes. Water was added to the reaction mixture, whichwas then acidified with 2 N hydrochloric acid. The crystals thusprecipitated were collected by filtration to obtain4-(4-chlorophenyl)-2-(4-methylphenylthio)-5-oxazolepropionic acid (1.73g, 93%). This was recrystallized from ethanol to give colorless needles.mp 160-161° C.

Example 12

In the same manner as in Example 11, obtained was4-(4-chlorophenyl)-2-(4-methyl-4H-1,2,4-triazol-3-ylthio)-5-oxazolepropionicacid (yield: 77%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with4-methyl-4H-1,2,4-triazole-3-thiol. This was recrystallized from ethanolto give pale brown needles. mp 186-188° C.

Example 13

In the same manner as in Example 11, obtained was4-(4-chlorophenyl)-2-(4-phenyl-4H-1,2,4-triazol-3-ylthio)-5-oxazolepropionicacid (yield: 61%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with4-phenyl-4H-1,2,4-triazole-3-thiol. This was recrystallized from ethanolto give colorless needles. mp 122-123° C.

Example 14

In the same manner as in Example 11, obtained was4-(4-chlorophenyl)-2-(1-phenyl-2-imidazolylthio)-5-oxazolepropionic acid(yield: 39%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with1-phenylimidazole-2-thiol. This was recrystallized from ethanol to givepale brown needles. mp 185-187° C.

Example 15

In the same manner as in Example 11, obtained was4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionic acid (yield:95%) by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acidwith 2-mercaptopyridine. This was recrystallized from ethanol an to givepale yellow needles. mp 172-173° C.

Example 16

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), an aqueous solution of 30% methylamine (4.0 ml) and 2-propanol (20ml) was stirred in a sealed tube at 100° C. for 4 hours. The reactionmixture was concentrated, and water was added to the resulting residue.The pH was then adjusted 3 with 2 N hydrochloric acid. The crystals thusprecipitated were collected by filtration to obtain4-(4-chlorophenyl)-2-methylamino-5-oxazolepropionic acid (1.21 g, 86%).This was recrystallized from ethanol to give colorless prisms. mp217-218° C.

Example 17

In the same manner as in Example 16, obtained was4-(4-chlorophenyl)-2-dimethylamino-5-oxazolepropionic acid (yield: 92%)by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid withdimethylamine. This was recrystallized from ethanol to give colorlessneedles. mp 189-190° C.

Example 18

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), morpholine (2.2 ml) and 2-propanol (20 ml) was stirred under refluxfor 4 hours. The reaction mixture was concentrated, and water was addedto the residue. The pH was then adjusted 3 with 2 N hydrochloric acid.The crystals thus precipitated were collected by filtration to obtain4-(4-chlorophenyl)-2-morpholino-5-oxazolepropionic acid (1.64 g, 98%).This was recrystallized from ethanol to give colorless needles. mp180-181° C.

Example 19

In the same manner as in Example 18, obtained was4-(4-chlorophenyl)-2-cyclohexylamino-5-oxazolepropionic acid (yield:53%) by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acidwith cyclohexylamine. This was recrystallized from ethanol to givecolorless needles. mp 237-238° C.

Example 20

In the same manner as in Example 18, obtained was4-(4-chlorophenyl)-2-(1-pyrrolidinyl)-5-oxazolepropionic acid (yield:99%) by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acidwith pyrrolidine. This was recrystallized from ethanol to give colorlessneedles. mp 199-200° C.

Example 21

In the same manner as in Example 18, obtained was4-(4-chlorophenyl)-2-piperidino-5-oxazolepropionic acid (yield: 97%) byreaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid withpiperidine. This was recrystallized from ethanol to give colorlessprisms. mp 185-186° C.

Example 22

In the same manner as in Example 18, obtained was4-(4-chlorophenyl)-2-(2-methylpiperidino)-5-oxazolepropionic acid(yield: 44%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with2-methylpiperidine. This was recrystallized from isopropyl ether to givecolorless prisms. mp 126-128° C.

Example 23

In the same manner as in Example 18, obtained was4-(4-chlorophenyl)-2-hexamethyleneimino-5-oxazolepropionic acid (yield:90%) by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acidwith hexamethyleneimine. This was recrystallized from ethanol to givecolorless prisms. mp 137-138° C.

Example 24

A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43g), imidazole (1.70 g), potassium carbonate (2.80 g) andN,N-dimethylformamide (15 ml) was stirred at 130° C. for 2.5 hours.Water was added to the reaction mixture. The pH was then adjusted 6 with2 N hydrochloric acid. The crystals thus precipitated were collected byfiltration to obtain4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropionic acid (1.35 g,85%). This was recrystallized from methanol to give colorless needles.mp 194-195° C.

Example 25

In the same manner as in Example 24, obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(yield: 54%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with2-methylimidazole. This was recrystallized from methanol to givecolorless needles. mp 195-197° C.

Example 26

In the same manner as in Example 24, obtained was4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-oxazolepropionic acid(yield: 88%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with2-ethylimidazole. This was recrystallized from methanol to givecolorless needles. mp 197-199° C.

Example 27

In the same manner as in Example 24, obtained was4-(4-chlorophenyl)-2-(2-phenyl-1-imidazolyl)-5-oxazolepropionic acid(yield: 29%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with2-phenylimidazole. This was recrystallized from ethanol to givecolorless needles. mp 179-180° C.

Example 28

In the same manner as in Example 24, obtained was4-(4-chlorophenyl)-2-(1-pyrazolyl)-5-oxazolepropionic acid (yield: 91%)by reaction of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid withpyrazole. This was recrystallized from methanol to give colorlessneedles. mp 171-172° C.

Example 29

In the same manner as in Example 24, obtained was4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionic acid(yield: 91%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid with 1,2,4-triazole.This was recrystallized from ethanol to give colorless prisms. m.p.168-169° C.

Example 30

Methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (1.50 g) and2-propylimidazole (0.66 g) were dissolved in N,N-dimethylformamide (10ml), and sodium hydride (60% dispersion in oil, 0.30 g) was graduallyadded to the resulting solution at room temperature. After this wasstirred at room temperature for 3.5 hours, an aqueous solution of 2 Nsodium hydroxide (50 ml) was added thereto and stirred for an additional30 minutes. Water was added to the reaction mixture, and the pH was thenadjusted to 6 with 2 N hydrochloric acid. The crystals thus precipitatedwere collected by filtration, and recrystallized from ethanol to obtain4-(4-chlorophenyl)-2-(2-propyl-1-imidazolyl)-5-oxazolepropionic acid(1.25 g, 69%) as pale brown needles. mp 174-175° C.

Example 31

In the same manner as in Example 30, obtained was4-(4-chlorophenyl)-2-(2-isopropyl-1-imidazolyl)-5-oxazolepropionic acid(yield: 59%) by reaction of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with2-isopropylimidazole followed by hydrolysis of the resulting product.This was recrystallized from ethyl acetate to give colorless prisms. mp173-174° C.

Example 32

In the same manner as in Example 30, obtained was4-(4-chlorophenyl)-2-(2-methylthio-1-imidazolyl)-5-oxazolep ropionicacid (yield: 87%) by reaction of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with2-methylthioimidazole followed by hydrolysis of the resulting product.This was recrystallized from chloroform-ethanol to give colorlessneedles. mp 225-226° C.

Example 33

In the same manner as in Example 30, obtained was4-(4-chlorophenyl)-2-(4,5-dimethyl-1-imidazolyl)-5-oxazolepropionic acid(yield: 77%) by reaction of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with4,5-dimethylimidazole followed by hydrolysis of the resulting product.This was recrystallized from chloroform-methanol to give pale brownneedles. mp 225-226° C.

Example 34

In the same manner as in Example 30, obtained was4-(4-chlorophenyl)-2-(1-benzimidazolyl)-5-oxazolepropionic acid (yield:82%) by reaction of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with benzimidazolefollowed by hydrolysis of the resulting product. This was recrystallizedfrom chloroform-methanol to give pale brown prisms. mp 217-218° C.

Example 35

In the same manner as in Example 30, obtained was4-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazolyl)-5-oxazolepropionic acid(yield: 90%) by reaction of methyl2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with3,5-dimethylpyrazole followed by hydrolysis of the resulting product.This was recrystallized from ethanol to give colorless needles. mp201-202° C.

Example 36

Lithium aluminium hydride (185 mg) was gradually added to atetrahydrofuran (20 ml) solution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(1.47 g) at room temperature. After the mixture was stirred for 1 hour,water (2 ml) was added to the reaction mixture with cooling with ice,and stirred for further 30 minutes. Diethyl ether (50 ml) was added tothe reaction mixture, which was then dried (MgSO₄), and the insolublesubstances were removed by filtration. The resulting filtrate wasconcentrated, and the crystals thus precipitated were collected byfiltration to obtain4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (435 mg,31%). This was recrystallized from dichloromethane-isopropyl ether togive colorless prisms. mp 128-129° C.

Example 37

In the same manner as in Example 36, obtained was4-(4-chlorophenyl)-2-(l-pyrazolyl)-5-oxazolepropanol (yield: 33%) byreduction of 4-(4-chlorophenyl)-2-(1-pyrazolyl)-5-oxazolepropionic acidwith lithium aluminium hydride. This was recrystallized from diethylether-hexane to give colorless prisms. mp 75-76° C.

Example 38

A toluene solution of diethyl azodicarboxylate (40%, 880 mg) wasdropwise added to a tetrahydrofuran (10 ml) solution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (320 mg),1,2,4-triazole (140 mg) and tributylphosphine (410 mg) at roomtemperature. After stirring for 1 hour, the reaction mixture wasconcentrated, and the residue was subjected to silica gel columnchromatography. From the fraction eluted with acetone-hexane (2:1, v/v),obtained was1-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]-1,2,4-triazole(305 mg, 82%). This was recrystallized from acetone-isopropyl ether togive colorless prisms. mp 142-143° C.

Example 39

In the same manner as in Example 38, obtained was4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl)-2-(2-methyl-1-imidazolyl)oxazole(yield: 54%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol with2-methoxyphenol. This was recrystallized from diethyl ether-hexane togive colorless needles. mp 84-85° C.

Example 40

In the same manner as in Example 38, obtained was3-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]-1-methylhydantoin(yield: 77%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol with1-methylhydantoin. This was recrystallized from acetone-isopropyl etherto give colorless prisms. mp 105-106° C.

Example 41

Ethyl chloroformate (395 mg) was dropwise added to a tetrahydrofuran (40ml) solution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(1.00 g) and triethylamine (365 mg), at −30° C. After stirring for 40minutes, the reaction mixture was added to a mixture of aqueous ammonia(28%, 30 ml) and tetrahydrofuran (10 ml) at 0° C., and then stirred atroom temperature for 1 hour. Water was added to the reaction mixture,and the crystals thus precipitated were collected by filtration toobtain4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (900mg, 90%). This was recrystallized from methanol-ethyl acetate to givecolorless needles. mp 215-216° C.

Example 42

Ethyl chloroformate (590 mg) was dropwise added to a tetrahydrofuran (40ml) solution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(1.50 g) and triethylamine (550 mg), at −30° C. After stirring for 30minutes, the reaction mixture was poured into a solution as preparedfrom 2-chloroethylamine hydrochloride (2.62 g), triethylamine (2.29 g)and N,N-dimethylformamide (20 ml), at 0° C., and then stirred at roomtemperature for 1 hour. The reaction mixture was poured into water, andthe crystals thus precipitated were collected by filtration to obtainN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(1.53 g, 86%). This was recrystallized from ethyl acetate-hexane to givecolorless needles. mp 155-156° C.

Example 43

In the same manner as in Example 42, obtained was-N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(l-imidazolyl)-5-oxazolepropionamide(yield: 77%) from 4-(4-chlorophenyl)-2-(l-imidazolyl)-5-oxazolepropionicacid. This was recrystallized from acetone-isopropyl ether to givecolorless needles. mp 130-131° C.

Example 44

In the same manner as in Example 42, obtained wasN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionamide(yield: 87%) from4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionic acid. Thiswas recrystallized from ethyl acetate-isopropyl ether to give colorlessneedles. mp 157-158° C.

Example 45

Ethyl chloroformate (435 mg) was dropwise added to a tetrahydrofuran (30ml) solution of 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionicacid (1.20 g) and triethylamine (405 mg), at −30° C. After stirring for30 minutes, the reaction mixture was poured into a solution as preparedfrom 2-chloroethylamine hydrochloride (1.93 g), triethylamine (1.68 g)and N,N-dimethylformamide (20 ml), at 0° C., and stirred at roomtemperature for 1 hour. The reaction mixture was poured into water, andthen extracted with ethyl acetate. The ethyl acetate layer was washedwith water, and dried (MgSO4), and the solvent was evaporated. Theresulting residue was subjected to silica gel column chromatography.From the fraction eluted with acetone-hexane (1:2, v/v), obtained wasN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionamide(1.29 g, 91%) as an oily substance.

NMR (δ ppm in CDCl₃): 2.65(2H,t,J=7.5 Hz), 3.29(2H,t,J=7.5 Hz),3.4-3.6(4 H,m), 6.24(1 H,brs), 7.21(1H,ddd,J=7.5&5&1 Hz), 7.35-7.5(3H,m), 7.6-7.75(3 H,m), 8.49(1H,dd,J=5&1 Hz).

Example 46

Sodium hydride (60% dispersion in oil, 265 mg) was gradually added to asolution of N-(2-chloroethyl)-4L(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (1.30g) in N,N-dimethylformamide (30 ml), at room temperature. After stirringat room temperature for 3 hours, the reaction mixture was poured intoice water, and then extracted with ethyl acetate. The ethyl acetatelayer was washed with water, and dried (MgSO4), and the solvent wasevaporated. The crystals thus precipitated were collected by filtrationto obtain4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[2-(2-oxazolin-2-yl)ethyl]oxazole(1.07 g, 91%). This was recrystallized from acetone-isopropyl ether togive colorless prisms. mp 119-120° C.

Example 47

In the same manner as in Example 46, obtained was4-(4-chlorophenyl)-2-(1-imidazolyl)-5-[2-(2-oxazolin-2-yl)ethyl]oxazole(yield: 69%) by cyclization ofN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropionamide.This was recrystallized from acetone-isopropyl ether to give colorlessprisms. mp 120-121° C.

Example 48

In the same manner as in Example 46, obtained was1-[4-(4-chlorophenyl)-5-[2-(2-oxazolin-2-yl)ethyl]-2-oxazolyl]-1,2,4-triazole(yield: 85%) by cyclization ofN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionamide.This was recrystallized from acetone-isopropyl ether to give colorlessprisms. mp 132-133° C.

Example 49

In the same manner as in Example 46,N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionamidewas cyclized, the reaction mixture was poured into water, and extracted,the resulting extract was washed with water and dried (MgSO₄), thesolvent was evaporated, and the resulting residue was subjected tosilica gel column chromatography. From the fraction eluted withacetone-hexane (1:2, v/v), obtained was4-(4-chlorophenyl)-2-(2-pyridylthio)-5-(2-(2-oxazolin-2-yl)ethyl]oxazoleas an oily substance (yield: 67%). NMR (δ ppm in CDCl₃): 2.65-2.8(2H,m), 3.2-3.35(2 H,m), 3.80(2H,t,J=9.5 Hz), 4.21(2H,t,J=9.5 Hz),7.16(1H,ddd,J=7.5&5&1 Hz), 7.35-7.45(3 H,m), 7.55-7.7(3 H,m),8.4(1H,ddd,J=5&2&0.5 Hz).

Example 50

Ethyl chloroformate (450 mg) was dropwise added to a tetrahydrofuran (40ml) solution of4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-oxazolepropionic acid(1.20 g) and triethylamine (420 mg), at −30° C. After stirring for 1hour, the reaction mixture was poured into a solution as prepared from2-chloroethylamine hydrochloride (2.01 g), triethylamine (1.76 g) andtetrahydrofuran (40 ml), at 0° C., and stirred at room temperature for1.5 hours. The reaction mixture was poured into water and then extractedwith ethyl acetate. The ethyl acetate layer was washed with water, anddried (with MgSO4), and the solvent was evaporated. The crystals (910mg) thus precipitated were collected by filtration. The crystals werestirred along with potassium carbonate (370 mg) in N,N-dimethylformamide(20 ml) at 90 to 100° C. for 1.5 hours. The reaction mixture was pouredinto water, and extracted with ethyl acetate. The ethyl acetate layerwas washed with water, and dried (MgSO₄), and the solvent wasevaporated. The resulting residue was subjected to silica gel columnchromatography. From the fraction eluted with acetone-hexane (2:3, v/v),obtained was4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[2-(2-oxazolin-2-yl)ethyl]oxazole(320 mg, 25%). This was recrystallized from isopropyl ether to givecolorless prisms. mp 53-54° C.

Example 51

In the same manner as in Example 50, obtained was4-(4-chlorophenyl)-5-[2-(2-oxazolin-2-yl)ethyl]-2-(1-pyrazolyl)oxazole(yield: 42%) by reaction of4-(4-chlorophenyl)-2-(1-pyrazolyl)-5-oxazolepropionic acid with2-chloroethylamine followed by cyclization of the resulting product.This was recrystallized from acetone-isopropyl ether to give colorlessneedles. mp 79-80° C.

Example 52

A mixture of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionicacid(500mg), potassium carbonate(310 mg), iodoethane(350mg) andN,N-dimethylformamide(10 ml) was stirred at room temperature for 16hours. Water was added to the mixture, and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The solvent was evaporated and the 15 crystalsthus precipitated were collected by filtration. These wererecrystallized from acetone-hexane to give colorless of ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate(495mg,91%). mp 70-71° C.

Example 53

In the same manner as Example 52, obtained was benzyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl) -5-oxazole propionate(yield: 88%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acidwith benzyl bromide. This was recrystallized from acetone-isopropylether to give colorless prisms. mp 71-72° C.

Example 54

In the same manner as Example 52, obtained was ethyl4-(4-chlorophenyl)-2-(l-imidazolyl)-5-oxazolepropionate (yield: 92%) byreaction of 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropionic acid35 with iodoethane. This was recrystallized from acetone-isopropyl etherto give colorless prisms. mp 67-68° C.

Example 55

In the same manner as Example 52, obtained was ethyl4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionate (yield:93%) by reaction of4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionic acid withiodoethane. This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 99-100° C.

Example 56

Water was added to a mixture which was obtained by ) reacting4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionic acid withiodoethane in the same manner as Example 52. This was extracted withethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The residue obtained by evaporated the solvent was subjected tosilica gel column chromatography. From the fraction eluted with ethylacetate-hexane (1:4, v/v), obtained was ethyl4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionate(yield: 96%) asan oily substance.

NMR(δ ppm in CDCl₃): 1.22(3H, t, J=7Hz), 2.74(2H, t, J=7.5Hz), 3.25(2H,t, J=7.5Hz), 4.12(2H, q, J=7Hz), 7.16(1H, ddd, J=7.5&5&1Hz),7.35-7.45(3H, m), 7.55-7.7(3H, m), 8.48(1H, ddd, J=5&2&1Hz).

Example 57

Lithium aluminum hydride (135mg) was gradually added to tetrahydrofuransolution (20ml) of ethyl4-(4-chlorophenyl)-2-(l-imidazolyl)-5-oxazolepropionate (1.15g) at 0C.After the reaction mixture was stirred for 2 hours, water was added tothe reaction mixture with cooling with ice. The insoluble material wasremoved by filtration, and then the filtrate was concentrated. Theresidue was subjected to silica gel column chromatography. From thefraction eluted with acetone-isopropyl ether (1:2, v/v), obtained was4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropanol (690mg, 68%). Thiswas recrystallized from acetone-isopropyl ether to give colorlessprisms. mp 114-115° C.

Example 58

In the same manner as Example 57, obtained was4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropanol(yield: 42%)by reduction of ethyl4-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-5-oxazolepropionate withlithium aluminum hydride. This was recrystallized frommethanol-isopropyl ether to give colorless prisms. mp 139-140° C.

Example 59

In the same manner as Example 57, obtained was4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropanol(yield: 81%) byreduction of ethyl4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionate with lithiumaluminum hydride. This was recrystallized from diethyl ether-isopropylether to give colorless prisms. mp 70-71° C.

Example 60

A mixture of4-(4-chlorophenyl)-5-(2-cyanoethyl)-2-(2-methyl-1-imidazolyl)oxazole(350mg), cysteamine (175mg) and 2-propanol was stirred under reflux for24 hours. Water was added to the reaction mixture, and the resultingmixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with water, and dried (MgSO₄). The residue obtained byevaporating the solvent was subjected to silica gel columnchromatography. From the fraction eluted with acetone-hexane (1:1, v/v),obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[2-(2-thiazolin-2-yl)ethyl]oxazole(320mg, 77%). This was recrystallized from acetone-isopropyl ether togive colorless prisms. mp 73-74° C.

Example 61

In the same manner as Example 1, obtained was methyl2-chloro-4-(4-chlorophenyl)-5-oxazolebutyrate(yield: 69%) by reaction ofmethyl 4-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]butyrate withphosphorus oxychloride. This was recrystallized from acetone-isopropylether to give colorless prisms. mp 73-74° C.

Example 62

In the same manner as Example 2, obtained was 2-chloro-4-(4-chlorophenyl)-5-oxazolebutyric acid(yield:

76%) by hydrolysis of methyl2-chloro-4-(4-chlorophenyl)--5-oxazolebutyrate. This was recrystallizedfrom acetone-ethyl acetate to give colorless prisms. mp 150-151° C.

Example 63

In the same manner as Example 24, obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazole butanoicacid(yield: 76%) by reaction of2-chloro-4-(4-chlorophenyl)-5-oxazolebutyric acid with2-methylimidazole. This was recrystallized from tetrahydrofuran-methanolto give colorless prisms. mp 211-212° C.

Example 64

In the same manner as Example 52, obtained was ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyrate(yield:88%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazole butyric acid withiodoethane. This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 72-73° C.

Example 65

Lithium aluminum hydride (110 mg) was gradually added to atetrahydrofuran solution (20ml) of ethyl4-(4-chloroethyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyrate (960mg) at0° C. After the mixture was stirred for 2 hours, water was added to thereaction mixture with cooling with ice. The insoluble material wasremoved by filtration, and then the filtrate was concentrated to obtain4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (750mg,88%). This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 110-111° C.

Example 66

Ethyl chloroformate (375mg) was added dropwise to a tetrahydrofuran(20ml)-N,N-dimethylformamide (10 ml) solution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoic acid(1.00 g) and triethylamine at −30° C. After stirring for 30 minutes, thereaction mixture was added to the solution of 2-chloroethylamine (1.45g)and N,N-dimethylformamide (20ml) at QOC. The resulting mixture wasstirred for 1 hour at room temperature. Water was poured into thereaction mixture to giveN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyramide(1.00 g, 85%). This was recrystallized from ethyl acetate-hexane to givecolorless needles. mp 131-132° C.

Example 67

Sodium hydride (60%, oil, 130mg) was gradually added to aN,N-dimethylformamide solution (30ml) ofN-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyramide(870mg) at room temperature. After stirring for 4 hours at roomtemperature, the reaction mixture was poured into ice water. And thiswas extracted with ethyl acetate. The ethyl acetate layer was washedwith water and dried (MgSO,).4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-oxazolin-2-yl)propyl]oxazole(615mg, 78%) was obtained by evaporating the solvent. This wasrecrystallized from acetone-isopropyl ether to give colorless prisms. mp88-89° C.

Example 68

Triethylamine(505 mg) was added dropwise to a N,N-dimethylformamidesolution of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionicacid(1.50 g) and N,O-dimethylhydroxyamine hydrochloride(490 mg) at 0° C.1-Hydroxybenzotriazole hydrate(HOBt, 760 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC, 950 mg)were added thereto. The reaction mixture was stirred for 20 hours atroom temperature. Water was poured into the reaction mixture. Saturatedsodium bicarbonate solution was added to make the mixture alkaline. Theresulting mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with water, and dried(MgSO₄). The solvent wasevaporated, and the precipitated crystals were collected by filtrationto giveN-methoxy-N-methyl-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(1.54g, 91%). This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 116-117° C.

Example 69

A toluene solution of diisobutylaluminum hydride(DIBAL-H, 1.0 M, 8.5 ml)was added dropwise into a tetrahydrofuran solution (40 ml) ofN-methoxy-N-methyl-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(800mg) at −70° C. After the reaction mixture was stirred for 3 hours, waterwas added to the reaction mixture. Acetic acid was added to make themixture neutral. The resulting mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with water, and dried(MgSO₄). Theresidue obtained by evaporating the solvent was subjected to silica gelcolumn chlomatography. From the fraction eluted with ethylacetate-hexane(1:3, v/v), obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionaldehyde(475mg, 70%). This was recrystallized from acetone-isopropyl ether ro givecolorless prisms. mp 109-110° C.

Example 70

A mixture of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionaldehyde(220mg), cysteamine(65 mg), p-toluensulfonic acid monohydrate(15 mg) andtoluene(20 ml) was stirred for 1 hour under reflux. Ethyl acetate wasadded to the reaction mixture. The ethyl acetate layer was separated,washed with water and then with a saturated sodium bicarbonate solution,and dried(MgSO₄). The residue obtained by evaporating the solvent wassubjected to silica gel column chlomatography. From the fraction elutedwith acetone-hexane(2:1, v/v), obtained was2-[2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]ethyl]thiazolidine(230 mg, 88%). This was recrystallized from acetone-isopropyl ether togive colorless prisms. mp 110-111° C.

Example 71

Methanesulfonyl chloride(215 mg) was added dropwise into atetrahydrofuran solution(20 ml) of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol(200 mg)and triethylamine(190 mg) at room temperature. After the reactionmixture was stirred for 12 hours, water was added to the reactionmixture. The resulting mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with water, and dried(MgSO₄). The residueobtained by evaporating the solvent was subjected to silica gel columnchromatography. From the fraction eluted with acetone-hexane(1:1, v/v),obtained was3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl)propylmethanesulfonate(180 mg, 72%). This was recrystallized fromacetone-isopropyl ether to give colorless prisms. mp 97-98° C.

Example 72

A mixture of3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propylmethanesulfonate(400 mg), imidazole(140 mg), potassium carbonate(280 mg)and N,N-dimethylformamide(20 ml) was stirred for 2 hours at 100-110° C.Water was added to the reaction mixture. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chromatography. From the fractioneluted with methanol-chloroform(5:95, v/v), obtained was4-(4-chlorophenyl)-5-[3-(1-imidazolyl)propyl]-2-(2-methyl-1-imidazolyl)oxazole(230mg, 62%). This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 133-134° C.

Example 73

In the same manner as Example 72, obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(1-pyrazolyl)propyl)oxazole(yield: 54%) by reaction of3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propylmethanesulfonate with pyrazole. This was recrystallized fromacetone-isopropyl ether to give colorless prisms. mp 129-130° C.

Example 74

In the same manner as Example 38, obtained was3-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]-2,4-oxazolidinedione(yield:89%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol with2,4-oxazolidinedione. This was recrystallized from acetone-isopropylether to give colorless prisms. mp 152-153° C.

Example 75

In the same manner as Example 38, obtained was3-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]-2,4-thiazolydinedione(yield:91%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol with2,4-thiazolidinedione. This was recrystallized from ethyl acetate-hexaneto give colorless needles. mp 119-120° C.

Example 76

In the same manner as Example 38, obtained was3-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]hydantoin(yield:65%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol withhydantoin. This was recrystallized from methanol-ethyl acetate to givecolorless prisms. mp 197-198° C.

Example 77

A mixture of ethyl2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-hydroxyacetate(1.30g) and thionyl chloride(3 ml) was stirred for 30 minutes at roomtemperature. The reaction mixture was concentrated. Saturated sodiumbicarbonate was added to the residue, and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The crystals(1.25 g) obtained by evaporatingthe solvent was collected by filtration. Zinc powder(5.0 g) was added toan acetic acid solution(10 ml) of the crystals(1.25 g). The resultingmixture was stirred for 1 hour at 100-110° C. The zinc powder wasremoved by filtration. The filtrate was concentrated. Saturated sodiumbicarbonate was added to the residue, and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chromatography. From the fractioneluted with ethyl acetate-hexane(2:3, v/v), obtained was ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazole acetate(960 mg,77%). This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 133-134° C.

Example 78

In the same manner as Example 57, obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolethanol (yield:48%) by reduction of ethyl4-(4-chlorophenyl)-2-(2-methyl-imidazolyl)-5-oxazole acetate withlithium aluminum hydride. This was recrystallized from acetone-isopropylether to give colorless prisms. mp 159-160° C.

Example 79

A mixture of ethyl5-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]pentanoate(17.2 g),phosphorus oxychloride(32.6 g) and pyridine(4.20 g) was stirred for 80minutes at 120-130° C. The reaction mixture was poured into ice water,and extracted with ethyl acetate. The ethyl acetate layer was washedwith water, and dried(MgSO₄). The residue obtained by evaporating thesolvent was subjected to silica gel column chlomatography. From thefraction eluted with ethyl acetate-hexane(1:3, v/v), obtained was ethyl2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate as an oilysubstance(14.1 g, 78%).

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7Hz), 1.6-1.85(4H, m), 2.34(2H, t,J=6.5Hz), 2.86(2H, t, J=7Hz), 4.13(2H, q, J=7Hz), 7.39(2H, d, J=8.5Hz),7.53(2H, d, J=8.5Hz).

Example 80

In the same manner as Example 79, obtained was ethyl2-chloro-4-(4-chlorophenyl)-5-oxazolehexanoate as an oily substance(yield: 70%) by reaction of ethyl6-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]hexanoate with phosphorusoxychloride.

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7Hz), 1.3-1.85(6H, m), 2.31(2H, t,J=7.5Hz), 2.85(2H, t, J=7.5Hz), 4.13(2H, q, J=7Hz), 7.39(2H, d,J=8.5Hz), 7.53(2H, d, J=8.5Hz).

Example 81

A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate(10.0g), 2-methylimidazole(7.20 g), potassium carbonate(12.1 g) andN,N-dimethylformamide(80 ml) was stirred for 2 hours at 120-130° C.Water was added to the reaction mixture to give 30 ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(9.97 g,88%). This was recrystallized from ethyl acetate-isopropyl ether to givecolorless prisms. mp 93-94° C.

Example 82

A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolehexanoate(3.53g), 2-methylimidazole(2.44 g), potassium carbonate(4.10 g) andN,N-dimethylformamide(50 ml) was stirred for 3 hours at 120-125° C.Water was added to the reaction mixture. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chlomatography. From the fractioneluted with ethyl acetate-hexane(1:1, v/v), obtained was ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolehexanoate as anoily substance(3.48 g, 87%).

NMR(δ ppm in CDCl₃): 1.25(3H, t, J=7Hz), 1.35-1.9(6H, m), 2.31(2H, t,J=7.5Hz), 2.77(3H, s), 2.91(2H, t, J=7.5Hz), 4.12(2H, q, J=7Hz),7.01(1H, d, J=l.5Hz), 7.42(2H, d, J=8.5Hz), 7.48(1H, d, J=1.5Hz),7.60(2H, d, J=8.5Hz).

Example 83

Lithium aluminum hydride(615 mg) was gradually added to atetrahydrofuran solution(80 ml) of ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(6.00 g)at 0° C. After the reaction mixture was stirred for 2 hours, water(1 ml)was added to the reaction mixture with cooling with ice, and theinsoluble substance was removed by filtration. The filtrate wasconcentrated to give4-(4-chlorophenyl)-2-(2-methyl-imidazolyl)-5-oxazolepentanol(4.20 g,79%). This was recrystallized from ethyl acetate to give colorlessprisms. mp 94-95° C.

Example 84

Lithium aluminum hydride(340 mg) was gradually added to atetrahydrofuran solution(40 ml) of ethyl4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolehexanoate(3.40 g)at 0° C. After the reaction mixture was stirred for 1 hour, water(1 ml)was added to the reaction mixture with cooling with ice, and theinsoluble substance was removed by filtration. The filtrate wasconcentrated. The residue was subjected to silica gel chlomatography.From the fraction eluted with acetone-hexane(1:1, v/v), obtained was4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolehexanol(2.74 g,90%). This was recrystallized from acetone-isopropyl ether to givecolorless prisms. mp 70-71° C.

Example 85

In the same manner as Example 71, obtained was4-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butylmethanesulfonate(yield: 85%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol withmethanesulfonyl chloride. This was recrystallized fromacetone-diethylether to give colorless prisms. mp 100-101° C.

Example 86

Methanesulfonyl chloride(1.43 g) was added dropwise to a tetrahydrofuransolution(40 ml) of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanol(2.16 g)and triethylamine(1.26 g) at room temperature. After the reactionmixture was stirred for 2 hours, water was added to the reactionmixture. The resulting mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with water, and dried(MgSO₄). The residueobtained by evaporating the solvent was subjected to silica gel columnchlomatography. From the fraction eluted with acetone-hexane(1:1, v/v),obtained was5-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]pentylmethanesulfonate as an oily substance(2.47 g, 93%).

NMR(δ ppm in CDCl₃): 1.45-1.9(6H, m), 2.78(3H, s), 2.94(2H, t, J=7.5Hz),3.00(3H, s), 4.24(2H, t, J=6Hz), 7.01(1H, d, J=1.5Hz), 7.43(2H, d,J=8.5Hz), 7.48(1H, d, J=1.5Hz), 7.60(2H, d, J=8.5Hz).

Example 87

In the same manner as Example 86, obtained was6-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]hexylmethanesulfonate as an oily substance(yield: 93%) by reaction of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolehexanol withmethanesulfonyl chloride.

NMR(δ ppm in CDCl₃): 1.4-1.9(8H, m), 2.78(3H, s), 2.92(2H, t, J=7.5Hz),3.00(3H, s), 4.23(2H, t, J=6.5Hz), 7.01(1H, d, J=1.5Hz), 7.43(2H, d,J=8.5Hz), 7.48(1H, d, J=1.5Hz), 7.61(2H, d, J=8.5Hz).

Example 88

Diethyl azodicarboxylate(260 mg) was added dropwise to a tetrahydrofuransolution(10 ml) of4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol(330 mg),1,2,4-triazole(105 mg) and tributylphosphine(300 mg) with cooling withice. After stirring for 1 hour, the reaction mixture was concentrated.The residue was subjected to silica gel column chlomatography. From thefraction eluted with methanol-chloroform(5:95, v/v), obtained was1-(4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butyl]1,2,4-triazole(205mg, 54%). This was recrystallized from ethyl acetate-diethyl ether togive colorless prisms. mp 74-75° C.

Example 89

A mixture of4-[4-(4-chlorophenyl)-2-(2-methyl-imidazolyl)-5-oxazolyl]butylmethanesulfonate(600 mg), imidazole(200 mg), potassium carbonate(405 mg)and N,N-dimethylformamide(10 ml) was stirred for 90 minutes at 100-110°C. Water was added to the reaction mixture. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chromatography. From the fractioneluted with methanol-chloroform(3:97, v/v), obtained was4-(4-chlorophenyl)-5-[4-(1-imidazolyl)butyl]-2-(2-methyl-1-imidazolyl)oxazole(310mg, 55%). This was recrystallized from ethyl acetate-diethyl ether togive colorless prisms. mp 84-85° C.

Example 90

A mixture of5-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]pentylmethanesulfonate(2.20 g), imidazole(710 mg), potassium carbonate(1.43 g)and N,N-dimethylformamide(40 ml) was stirred for 3 hours at 80-90° C.Water was added to the reaction mixture. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporated the solventwas subjected to silica gel column chromatography. From the fractioneluted with methanol-chloroform(3:97, v/v), obtained was4-(4-chlorophenyl)-5-[5-(1-imidazolyl)pentyl]-2-(2-methyl-1-imidazolyl)oxazole(1.45g, 71%). The oily substance(1.45 g) was dissolved in methanol(6 ml), andthereto a 4N-hydrochloric acid-ethyl acetate solution (2 ml) was added.Ethyl acetate was then added to the reaction mixture. The precipitatedwhite powder was collected by filtration, and washed with ethylacetate-acetone to give4-(4-chlorophenyl)-5-[5-(1-imidazolyl)pentyl]-2-(2-methyl-1-imidazolyl)oxazoledihydrochloride monohydrate(l.47 g, 58%). mp 197-199° C.

Example 91

A mixture of6-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]hexylmethansulfonate(2.11 g), imidazole(660 mg), potassium carbonate(1.33 g)and N,N-dimethylformamide(40 ml) was stirred for 2 hours at 90-95° C.Water was added to the reaction mixture. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, and dried(MgSO₄). The residue obtained by evaporating the solventwas subjected to silica gel column chromatography. From the fractioneluted with methanol-chloroform(3:97, v/v), obtained was4-(4-chlorophenyl)-5-[6-(i-imidazolyl)hexyl]-2-(2-methyl-1-imidazolyl)oxazole(1.26g, 64%). The oily substance (1.26 g) was dissolved in methanol(5 ml),and thereto a 4N-hydrochloric acid-ethyl acetate solution (1.7 ml) wasadded. The reaction mixture was concentrated. Ethyl acetate was added tothe residue. The precipitated white powder was collected by filtration.This was recrystallized from methanol-acetone to give4-(4-chlorophenyl)-5-[6-(l-imidazolyl)hexyl]-2-(2-methyl-1-imidazolyl)oxazoledihydrochloride hemihydrate(1.16 g, 49%). mp 171-173° C.

Example 92

A mixture of4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butylmethanesulfonate( 600 mg), ethyl 2-imidazolecarboxylate(410 mg),potassium carbonate(405 mg) and N,N-dimethylformamide (30 ml) wasstirred for 2 hours at 80-90° C. Water was added to the reactionmixture. This was extracted with ethyl acetate. The ethyl acetate layerwas washed with water and dried (Mg SO₄). The residue obtained byevaporating the solvent was subjected to silica gel columnchromatography. From the fraction eluted with acetone-hexane (1:1, v/v),obtained was ethyl1-[4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butyl)-2-imidazolecarboxylateas crystals (460 mg, 69%). This was recrystallized fromacetone-isopropyl ether to give colorless prisms. mp 134-135° C.

Formulation Example 1 (production of tablets):

(1) 4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl) 30 g -5-oxazolepropanol(compound produced in Example 36) (2) Lactose 50 g (3) Corn Starch 15 g(4) Carboxymethyl Cellulose 44 g (5) Magnesium Stearate  1 g 1000tablets 140 g 

All of (1), (2) and (3), and 30 g of (4) were kneaded with water, thendried in vacuum and granulated. To the resulting granules, added were 14g of (4) and 1 g of (5), mixed and tabletted, using a tablettingmachine, into tablets. Thus were produced 1000 tablets each containing30 mg/tablet of (1).

Formulation Example 2 (production of tablets):

(1) 4-(4-Chlorophenyl)-5-[2-(2-oxazolin-2- 100 gyl)ethyl]-2-(1-pyrazolyl)oxazole (compound produced in Example 51) (2)Lactose 200 g (3) Corn Starch  55 g (4) Carboxymethyl Cellulose  44 g(5) Magnesium Stearate  1 g 1000 tablets 400 g

All of (1), (2) and (3), and 30 g of (4) were kneaded with water, thendried in vacuum and granulated. To the resulting granules, added were 14g of (4) and 1 g of (5), mixed and tabletted, using a tablettingmachine, into tablets. Thus were produced 1000 tablets each containing100 mg/tablet of (1).

INDUSTRIAL APPLICABILITY

The compounds (I) or their salts of the present invention have anexcellent blood sugar-depressing effect and an insulinsecretion-promoting effect, and are poorly toxic. The compounds (I) ortheir salts of the present invention are useful in insulin secretionpromoting agents for diabetes, agents for arteriosclerosis, agents forhyperlipemia, depressors, and agents for diabetic complications (e.g.,nephropathy, retinopathy, neuropathy).

What is claimed is:
 1. A compound represented by the formula:

wherein R¹ is an optionally substituted heterocyclic group; A is anoptionally substituted heterocyclic group; B is an optionallysubstituted aromatic group; Y is a divalent aliphatic hydrocarbon group;or a salt thereof.
 2. A compound as claimed in claim 1, wherein theheterocyclic group for R¹ is: a 5- or 6-membered ring having as ringconstituting atoms carbon atom(s) and 1 to 4 atoms selected from thegroup consisting of N, O and S as the, or a condensed ring comprisingthe 5- or 6-membered ring condensed with any of a 6-membered ring having1 or 2 nitrogen ring-constituting atoms, a benzene ring or a 5-memberedring having one sulfur ring-constituting atom.
 3. A compound as claimedin claim 1, wherein the heterocyclic group for R¹ is an azolyl group. 4.A compound as claimed in claim 1, wherein A is an optionally substitutedheterocyclic group.
 5. A compound as claimed in claim 4, where in theheterocyclic group is a 5- or 6-membered ring having 1 to 4 atomsselected from N, O and S as the ring-constituting atoms other thancarbon atom(s), or a condensed ring comprising the 5- or 6-membered ringas condensed with any of a 6-membered ring having 1 or 2 nitrogen, abenzene ring or a 5-membered ring having one sulfur.
 6. A compound asclaimed in claim 4, wherein the heterocyclic group is an azolyl,azolinyl or azolidinyl group.
 7. A compound as claimed in claim 1 or 4,wherein R¹ and A are independently selected from the group consisting of2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl,2-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,tetrazol-1-yl, tetrazol-5-yl, benzimidazol-1-yl, benzimidazol-2-yl,indol-1-yl, indol-3-yl, 1H-indazol-1-yl, 1H-pyrrolopyrazin-1-yl,1H-pyrrolopyridin-1-yl, 1H-imidazopyridin-1-yl, 1H-imidazopyridin-1-yl,1H-imidazopyrazin-1-yl, 1-pyrrolidinyl, piperidino, morpholino,1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl,thiazolidin-3-yl, imidazolidin-3-yl, imidazolin-1-yl, imidazolin-2-yl,oxazolin-2-yl, thiazolin-2-yl, oxazin-2-yl, 2-oxoimidazolidin-1-yl,2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl and2,4-dioxothiazolidin-3-yl group which may be substituted by 1 to 3substitutents selected from the group consisting of an aliphatichydrocarbon group, an alicyclic hydrocarbon group, an aryl group, anaromatic heterocyclic group, a non-aromatic heterocyclic group, halogenatom, nitro group, an optionally substituted amino group, an optionallysubstituted acyl group, an optionally substituted hydroxy group, anoptionally substituted thiol group and an optionally esterified oramidated carboxy group.
 8. A compound as claimed in claim 1, wherein R¹is a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,benzimidazolyl, indolyl, 1H-indazolyl, 1H-pyrrolopyrazinyl,1H-pyrrolopyridyl, 1H-imidazopyridyl, 1H-imidazopyridyl,1H-imidazopyrazinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl or oxazinyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of (i) a C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl group,(ii) a C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkenyl, or C₄₋₁₀ cycloalkadienylgroup, (iii) a C₆₋₁₄ aryl group, (iv) a furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl,benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolopyridazinyl,pyrazolopyridyl, imidazopyridyl, imidazopyridyl, imidazopyridazinyl,imidazopyrimidinyl, 1,2,4-triazolopyridyl, or 1,2,4-triazolopyridazinylgroup, (v) an oxiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl or pyrrolidinyl group, wherein each of saidgroups (ii), (iii), (iv) and (v) may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, thienyl, furyl,pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl, morpholino, piperidino,pyrrolidino, piperazino, C₇₋₉ aralkyl, amino, N-mono-C₁₋₄ alkylamino,N,N-di-C₁₋₄ alkylamino, C₂₋₈, acylamino, amidino, C₂₋₈ acyl, carbamoyl,N-mono-C₁₋₄ alkyl-carbamoyl, N,N-di-C₁₋₄ alkyl-carbamoyl, sulfamoyl,N-mono-C₁₋₄ alkylsulfamoyl, N,N-di-C₁₋₄ alkylsulfamoyl, carboxy, C₁₋₇alkoxy-carbonyl, hydroxy, C₁₋₄ alkoxy, C₂₋₅ alkenyloxy, C₃₋₇cyloalkyloxy, C₇₋₉ aralkyloxy, C₆₋₁₄ aryloxy, mercapto, C₁₋₄ alkylthio,C₇₋₉ aralkylthio, C₆₋₁₄ arylthio, sulfo, cyano, azido, nitro, nitrosoand halogen, (vi) halogen atom, (vii) nitro group, (viii) an amino groupwhich may be substituted by 1 or 2 substituents selected from the groupconsisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkyl, C₁₋₁₀ acyland C₆₋₁₂ aryl, (ix) a C₁₋₁₃ acyl group which may be substituted by aC₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, nitro, hydroxy or amino, (x) a hydroxygroup, a C₁₋₁₀ alkoxy group, a C₂₋₁₀ alkenyloxy group, a C7-10aralkyloxy group, a C₂₋₁₃ acyloxy group, a C₆₋₁₄ aryloxy group which maybe substituted by 1 or 2 halogen or C₁₋₄ alkoxy, a C₁₋₁₀alkylsulfonyloxy group or a C₆₋₁₂ arylsulfonyloxy group which may besubstituted by a C₁₋₆ alkyl, (xi) a mercapto or C₁₋₁₀ alkylthio groupwhich may be substituted by a furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl,benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolopyridazinyl,pyrazolopyridyl, imidazopyridyl, imidazopyridyl, imidazopyridazinyl,imidazopyrimidinyl, 1,2,4-triazolopyridyl or 1,2,4-triazolopyridazinyl,a C₆₋₁₄ arylthio group which may be substituted by C₁₋₆ alkyl, a C₇₋₁₀aralkylthio group, or a C₂₋₁₃ acylthio group, (xii) a carboxy group, aC₁₋₄ alkoxy-carbonyl group, a C₇₋₉ aralkyloxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group, or a C₁₋₄ alkoxy-carbonyl group substituted by afuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl; phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolopyridazinyl, pyrazolopyridyl, imidazopyridyl,imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl,1,2,4-triazolopyridyl or 1,2,4-triazolopyridazinyl, (xiii) a group ofthe formula: —CON(R⁵)(R⁶) wherein R⁵ and R⁶ independently are ahydrogen; a C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl; a C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkadienyl, C₆₋₁₄ aryl,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolopyridazinyl, pyrazolopyridyl, imidazopyridyl,imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl,1,2,4-triazolopyridyl, or 1,2,4-triazolopyridazinyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl,morpholino, piperidino, pyrrolidino, piperazino, C₇₋₉ aralkyl, amino,N-mono-C₁₋₄ alkylamino, N,N-di-C₁₋₄ acylamino, C₂₋₈ acylamino, amidino,C₂₋₈ acyl, carbamoyl, N-mono-C₁₋₄ alkylcarbamoyl, N,N-di-C₁₋₄alkylcarbamoyl, sulfamoyl, N-mono-C₁₋₄ alkylsulfamoyl, N,N-di-C₁₋₄alkylsulfamoyl, carboxy, C₂₋₈ alkoxycarbonyl, hydroxy, C₁₋₄ alkoxy, C₂₋₅alkenyloxy, C₃₋₇ cyloalkyloxy, C₇₋₉ aralkyloxy, C₆₋₁₄ aryloxy, mercapto,C₁₋₄ alkylthio, C₇₋₉ aralkylthio, C₆₋₁₄ arylthio, sulfo, cyano, azido,nitro, nitroso and halogen; or a hydroxy, C₁₋₁₀ alkoxy, C₂₋₁₀alkenyloxy, C₇₋₁₀ aralkyloxy, C₂₋₁₃ acyloxy, C₆₋₁₄ aryloxy which may besubstituted by 1 or 2 halogen or C₁₋₄ alkoxy or C₁₋₁₀ alkylsulfonyloxygroup, and (xiv) an oxo group.
 9. A compound as claimed in, claim 1,wherein A is a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,benzimidazolyl, indolyl, 1H-indazolyl, 1H-pyrrolopyrazinyl,1H-pyrrolopyridyl, 1H-imidazopyridyl, 1H-imidazopyridyl,1H-imidazopyrazinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl or oxazinyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of (i) a C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl group,(ii) a C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkenyl, or C₄₋₁₀ cycloalkadienylgroup, (iii) a C₆₋₁₄ aryl group, (iv) a furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl,benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolopyridazinyl,pyrazolopyridyl, imidazopyridyl, imidazopyridyl, imidazopyridazinyl,imidazopyrimidinyl, 1,2,4-triazolopyridyl, or 1,2,4-triazolopyridazinylgroup, (v) an oxiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl or pyrrolidinyl group, and each of saidgroups (ii), (iii), (iv) and (v) may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, thienyl, furyl,pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl, morpholino, piperidino,pyrrolidino, piperazino, C₇₋₉ aralkyl, amino, N-mono-C₁₋₄ alkylamino,N,N-di-C₁₋₄ alkylamino, C₂₋₈ acylamino, amidino, C₂₋₈ acyl, carbamoyl,N-mono-C1-4 alkyl-carbamoyl, N,N-di-C₁₋₄ alkyl-carbamoyl, sulfamoyl,N-mono-C₁₋₄ alkylsulfamoyl, N,N-di-C₋₄ alkylsulfamoyl, carboxy, C₁₋₇alkoxycarbonyl, hydroxy, C₁₋₄ alkoxy, C₂₋₅ alkenyloxy, C₃₋₇cyloalkyloxy, C₇₋₉ aralkyloxy, C₆₋₁₄ aryloxy, mercapto, C₁₋₄ alkylthio,C₇₋₉ aralkylthio, C₆₋₁₄ arylthio, sulfo, cyano, azido, nitro, nitrosoand halogen, (vi) halogen atom, (vii) nitro group, (viii) an amino groupwhich may be substituted by 1 or 2 substituents selected from the groupconsisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkyl, C₁₋₁₀ acyland C₆₋₁₂ aryl, (ix) a C₁₋₁₃ acyl group which may be substituted by aC₁₋₃ alkyl, C₁₋₃ alkoxy, halogen, nitro, hydroxy or amino, (x) a hydroxygroup, a C₁₋₁₀ alkoxy group, a C₂₋₁₀ alkenyloxy group, a C₇₋₁₀aralkyloxy group, a C₂₋₁₃ acyloxy group, a C₆₋₁₄ aryloxy group which maybe substituted by 1 or 2 halogen or C₁₋₄ alkoxy, a C₁₋₁₀alkylsulfonyloxy group or a C₆₋₁₂ arylsulfonyloxy group which may besubstituted by a C₁₋₆ alkyl, (xi) a mercapto or C₁₋₁₀ alkylthio groupwhich may be substituted by a furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl,benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-cabolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolopyridazinyl,pyrazolopyridyl, imidazopyridyl, imidazopyridyl, imidazopyridazinyl,imidazopyrimidinyl, 1,2,4-triazolopyridyl or 1,2,4-triazolopyridazinyl,a C₆₋₁₄ arylthio group which may be substituted by C₁₋₆ alkyl, a C₇₋₁₀aralkylthio group, or C₂₋₁₃ acylthio group, (xii) a carboxy, a C₁₋₁₄alkoxy-carbonyl group, a C₇₋₉ aralkyloxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group, or a C₁₋₄ alkoxy-carbonyl group substituted by afuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolopyridazinyl, pyrazolopyridyl, imidazopyridyl,imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl,1,2,4-triazolopyridyl or 1,2,4-triazolopyridazinyl, (xiii) a group ofthe formula: —CON(R⁵)(R⁶) wherein R⁵ and R⁶ independently are ahydrogen, a C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl or a C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkadienyl, C₆₋₁₄ aryl,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolopyridazinyl, pyrazolopyridyl, imidazopyridyl,imidazopyrdyl, imidazopyridazinyl, imidazopyrimidinyl,1,2,4-triazolopyridyl, or 1,2,4-triazolopyridazinyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrahydrofuryl,morpholino, piperidino, pyrrolidino, piperazino, C₇₋₉ aralkyl, amino,N-mono-C₁₋₄ alkylamino, N,N-di-C₁₋₄ alkylamino, C₂₋₈ acylamino, amidino,C₂₋₈ acyl, carbamoyl, N-mono-C₁₋₄ alkylcarbamoyl, N,N-di-C₁₋₄alkylcarbamoyl, sulfamoyl, N-mono-C₁₋₄ alkylsulfamoyl, N,N-di-C₁₋₄alkylsulfamoyl, carboxy, C₂₋₈ alkoxycarbonyl, hydroxy, C₁₋₄ alkoxy, C₂₋₅alkenyloxy, C₃₋₇ cyloalkyloxy, C₇₋₉ aralkyloxy, C₆₋₁₄ aryloxy, mercapto,C₁₋₄ alkylthio, C₇₋₉ aralkylthio, C₆₋₁₄ arylthio, sulfo, cyano, azido,nitro, nitroso and halogen; or a hydroxy, C₁₋₁₀ alkoxy, C₂₋₁₀alkenyloxy, C₇₋₁₀ aralkyloxy, C₂₋₁₃ acyloxy, C₆₋₁₄ aryloxy which may besubstituted by 1 or 2 halogen or C₁₋₄ alkoxy, or C₁₋₁₀ alkylsulfonyloxygroup.
 10. A compound as claimed in claim 1, wherein B is a C₆₋₁₄ aryl,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolopyridazinyl, pyrazolopyridyl, imidazopyridyl,imidazopyridyl, imidazopyridazinyl, imidazopyrimidinyl,1,2,4-triazolopyridyl, or 1,2,4-triazolopyridazinyl group which may besubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, nitro, cyano, C₁₋₆ alkoxy which may be substituted by 1 to 3halogen, hydroxy or C₁₋₆ alkoxy, C₁₋₆ alkyl which may be substituted by1 to 3 halogen, hydroxy or C₁₋₆ alkoxy, C₃₋₇ cycloalkyl which may besubstituted by 1 to 3 halogen, hydroxy or C₁₋₆ alkoxy.
 11. A compound asclaimed in claim 1, wherein Y is a divalent aliphatic hydrocarbon grouphaving 1 to 7 carbon atoms.
 12. A compound as claimed in claim 1,wherein Y is a divalent aliphatic hydrocarbon group having 2 to 4 carbonatoms.
 13. A compound as claimed in claim 1, wherein R¹ is animidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, benzimidazolyl,pyrrolidinyl, piperidinyl, morpholinyl, or hexamethyleneiminyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of C₁₋₁₀ alkyl, C₆₋₁₄ aryl and C₁₋₁₀ alkylthio, A is animidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl,oxazolinyl, thiazolinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinylor 2,4-dioxothiazolidinyl group which may be substituted by a C₁₋₁₀alkyl; B is a phenyl group which may be substituted by a halogen; Y is-(CH₂)₂-, -(CH₂)₃-, -(CH₂)₄-, -(CH₂)₅- or -(CH₂)₆-.
 14. A compound asclaimed in claim 1, wherein A is an optionally substituted heterocyclicgroup; and Y is a divalent aliphatic hydrocarbon group having 1 to 7carbon atoms.
 15. A compound as claimed in claim 14, wherein each of theheterocyclic group represented by R¹ and A is an azolyl group, anazolinyl group or an azolidinyl group.
 16. A compound as claimed inclaim 6, wherein the heterocyclic group represented by R¹ is an azolylgroup, and the heterocyclic group represented by A is an azolyl group,an azolinyl group or an azolidinyl group.
 17. A compound as claimed inclaim 14, wherein R¹ and A are independently a pyrrolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, imidazolinyl,oxazolinyl or thiazolinyl group which may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₁₀ alkyl, C₆₋₁₄aryl, C₁₋₁₀ alkylthio and oxo.
 18. A compound as claimed in claim 14,wherein R¹ is an azolyl group which may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₁₀ alkyl, C₆₋₁₄aryl and C₁₋₁₀ alkylthio.
 19. A compound as claimed in claim 18, whereinthe azolyl group is an imidazolyl, pyrazolyl, 1,2,4-triazolyl, or1,2,3-triazolyl group.
 20. A compound as claimed in claim 14, wherein Ais an azolyl, azolinyl or azolidinyl group which may be substituted by 1or 2 C₁₋₁₀ alkyl or oxo.
 21. A compound as claimed in claim 14, whereinA is an imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,thiazolidinyl, oxazolinyl, thiazolinyl, 2,4-dioxoimidazolidinyl,2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group which may besubstituted by a C₁₋₁₀ alkyl.
 22. A compound as claimed in claim 14,wherein B is an optionally substituted phenyl group.
 23. A compound asclaimed in claim 14, wherein B is a phenyl group which may besubstituted by a halogen.
 24. A compound as claimed in claim 14, whereinY is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms.25. A compound as claimed in claim 14, wherein Y is -(CH₂)₃-, -(CH₂)₄-or -(CH₂)₅-.
 26. A compound as claimed in claim 1, which4-(4-chlorophenyl)-5-[3-(1-imidazolyl)propyl]-2-(2-methyl-1-imidazolyl)oxazoleor its salt.
 27. A compound as claimed in claim 1, which4-(4-chlorophenyl)-5-(4-(1-imidazolyl)butyl]-2-(2-methyl-1-imidazolyl)oxazoleor its salt.
 28. A process for producing a compound represented by theformula:

wherein R^(1b) is an optionally substituted heterocyclic group and theother symbols are of the same meanings as defined in claim 1, or a saltthereof, which comprises reacting a compound represented by the formula:

wherein R^(1a) is a halogen atom, or a salt thereof with a compoundrepresented by the formula: R^(1b)-H or a salt thereof.
 29. Apharmaceutical composition comprising a compound as claimed in claim 1.30. A composition as claimed in claim 29, which is an insulinsecretion-promoting agent.
 31. A composition as claimed in claim 29,which is an agent preventing and treating for diabetes.
 32. A compoundas claimed in claim 1, wherein R¹ is 2-methyl-1-imidazolyl.
 33. Acompound as claimed in claim 1, wherein B is 4-chlorophenyl.
 34. Acompound as claimed in claim 32, wherein B is 4-chlorophenyl.
 35. Acompound as claimed in claim 1, wherein Y is propylene.
 36. A compoundas claimed in claim 33, wherein Y is propylene.
 37. A method formanufacturing a medicament for the prophylaxis or treatment of diabetes,comprising selecting a compound according to claim 1 and admixing saidcompound with a pharmaceutically acceptable excipient.
 38. A method forpreventing or treating diabetic complications in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound as claimed in claim
 1. 39. A compound as claimed inclaim 34, wherein Y is propylene.